Download Drug-Metabolizing Enzymes: Mechanisms and Functions

Current Drug Metabolism, 2000, 1, 107-132
107
Drug-Metabolizing Enzymes: Mechanisms and Functions
Salah A. Sheweita*
Department of Bioscience and Technology, Institute of Graduate Studies and Research, 163
Horreya Ave., PO Box 832, Alexandria University, Egypt
Abstract: Drug-metabolizing enzymes are called mixed-function oxidase or
monooxygenase and containing many enzymes including cytochrome P450, cytochrome
b5, and NADPH-cytochrome P450 reductase and other components. The hepatic
cytochrome P450s (Cyp) are a multigene family of enzymes that play a critical role in the
metabolism of many drugs and xenobiotics with each cytochrome isozyme responding
differently to exogenous chemicals in terms of its induction and inhibition. For example,
Cyp 1A1 is particularly active towards polycyclic aromatic hydrocarbons (PAHs), activating them into
reactive intermediates those covalently bind to DNA, a key event in the initiation of carcinogenesis. Likewise,
Cyp 1A2 activates a variety of bladder carcinogens, such as aromatic amines and amides. Also, some forms of
cytochrome P450 isozymes such as Cyp 3A and 2E1 activate the naturally occurring carcinogens (e.g.
aflatoxin B1) and N-nitrosamines respectively into highly mutagenic and carcinogenic agents. The
carcinogenic potency of PAHs, and other carcinogens and the extent of binding of their ultimate metabolites
to DNA and proteins are correlated with the induction of cytochrome P450 isozymes.
Phase II drug-metabolizing enzymes such as glutathione S-transferase, aryl sulfatase and UDP-glucuronyl
transferase inactivate chemical carcinogens into less toxic or inactive metabolites. Many drugs change the rate
of activation or detoxification of carcinogens by changing the activities of phases I and II drug-metabolizing
enzymes. The balance of detoxification and activation reactions depends on the chemical structure of the
agents, and is subjected to many variables that are a function of this structure, or genetic background, sex,
endocrine status, age, diet, and the presence of other chemicals. It is important to realize that the enzymes
involved in carcinogen metabolism are also involved in the metabolism of a variety of substrates, and thus the
introduction of specific xenobiotics may change the operating level and the existence of other chemicals. The
mechanisms of modification of drug-metabolizing enzyme activities and their role in the activation and
detoxification of xenobiotics and carcinogens have been discussed in the text.
1.
DRUG-METABOLIZING ENZYMES
Monooxygenase is involved in the oxidation of
a wide range of substrates at the expense of
molecular oxygen since one atom of the molecular
oxygen enters the substrate and the other forms
water, such a reaction being known as a monooxygenase or mixed-function oxidase reaction [1].
The main components of the mixed function
oxidases (MFO) enzymes system are the
cytochrome P-450 isoenzymes [2]. The name was
given because the reduced form binds with carbon
monoxide to give a complex with maximum
absorption at 450 nm (3,4). Costas and Dennis in
1987, indicated that the cytochrome P-450 acts as
the terminal oxygenases of the mixed-function
oxidase systems of bacteria, yeast, plants, insects,
fishes and other vertebrates. MFO catalyzes the
*Address correspondence to this author at the Department of Bioscience and
Technology, Institute of Graduate Studies and Research, 163 Horreya Ave.,
PO Box 832, Alexandria University, Egypt; Tel: No. 203-422-5007; Fax:
203-421-5792; E-mail: [email protected]
1389-2000/00 $25.00+.00
oxidation, and reduction of numerous endogenous
and exogenous substances of widely diverse
chemical structure [5]. In addition, they are also
involved in the biosynthesis of cholesterol, steroid
hormones, bile acids and the oxidative metabolism
of fatty acids, lipophilic drugs and other chemical
(6-8). Many forms of cytochrome P-450 have been
isolated from both rodents and human tissues, and
they have been classified into 17 families
according to homologies of their amino acids
sequences [9,10].
Another member of the hepatic monooxygenase
system is NADPH-cytochrome P-450 reductase,
which was firstly observed in whole liver by
Horecker (1950) [11] and also in microsomes by
Strittmater and Velic in 1956 [12]. The prosthetic
group was identified as FAD (13-15). In addition
to cytochrome P-450 and NADPH-cytochrome P450 reductase, the mixed-function oxidase
contains also cytochrome b5 and NADHcytochrome b 5 reductase. The possible role of both
© 2000 Bentham Science Publishers Ltd.
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Current Drug Metabolism, 2000, Vol. 1, No. 2
in the cytochrome P-450-dependent reactions is
well known now than before (16-19].
1.1 FACTORS
ACTIVITY OF
ENZYMES
1.1.1
AFFECTING
THE
DRUG-METABOLIZING
Organs
Lung
Extrahepatic tissues have received relatively
less attention than liver because of their low levels
of mixed function oxidase activity [20]. The
ethoxyresourfin O-deethylase (EROD) activity
was lower in the lung than in the liver of rats [21].
Low levels of EROD activity were also detected in
rabbit lung [22]. The lower EROD activity in lung
compared to liver was confirmed using
monoclonal antibodies against cytochrome
P4501A1 [23]. Pulmonary levels of cytochrome
P450 1A1 were found to be < 3% of the total
microsomal cytochromes P-450 using the more
sensitive Western blotting technique. EROD
activity was induced after pretreatment of rats with
3-methylcholanthrene (MC) and 7,12-dimethylbenz(a)anthracene, and to a lesser extent by βnaphtoflavone (β-NF) [24-26]. A major form of
pulmonary cytochrome P-450, different from the
hepatic proteins, has been purified from rats after
MC treatment, which catalyzed the oxidation of
benzo (a) pyrene to various phenols, diols, and
quinines [27,28].
Similarly, the pulmonary levels of total
hemoprotein and aryl hydrocarbon hydroxylase
activity were increased after pretreatment of
rabbits with MC [29]. The extent of induction in
the lung of rabbit was low compared with that seen
in the liver [29]. Moreover, tetrachlorodibenzo-pdioxin (TCDD) and polychlorinated biphenyl
(PCB) increased the pulmonary EROD activity
and cytochrome P450 1A1 isozymes [30-35.].
Similarly, the inducibility of cytochrome P-450
1A2 in mouse lung by MC was studied using a
monoclonal antibody raised against the rat hepatic
cytochrome, which cross-reacted with the maurine
pulmonary cytochrome P450 1A1. In MC-induced
mice, cytochrome P450 1A was present in lung
and hepatic parenchyma cells, but this isoenzyme
was not detected in untreated or PB-induced lungs.
Treatment of hamster with MC, β-NF, or PCB
stimulated the activity of aryl hydrocarbon
hydroxylase [AHH] in lung, whereas hepatic
levels were not changed [36-39]. Induction of
AHH activity by these agents may partly explain
Salah A. Sheweita
why the hamster is more susceptible to tumors of
the respiratory tract than other animals [40].
Kidney
The cytochrome P-4501A isozymes were
detected in kidney but at levels markedly lower
than those seen in liver of rats using monoclonal
antibodies recognizing MC-induced cytochromes
[41,42]. The lower activity of cytochrome P450
1A in kidney was induced after treatments of rats
with either PAH, β-NF, or 2-AAF [43,44]. With
TCDD as inducing agent, immuno quantification
showed a marked increase in cytochrome
P4501A1, which accounted for 30% of total rat
kidney cytochrome P-450. Similarly, agents such
as alcohol induced cytochrome P450 2E1 in the
kidney [45].
1.1.2
Immunological Aspects
Monoclonal
antibodies
allowed
rapid
identification and quantification of cytochromes
belonging to the same gene family [46]. Nine
monoclonal antibodies have been raised against
cytochrome P4501A1 and reacting with six
distinct epitopes, one of them was shared with
cytochrome P4501A2 [46,47]. Cytochrome
P4501A1 was detected at low levels in the liver of
rats and at relatively higher levels in rabbit and
guinea pig livers, whereas a protein that relate to
cytochrome P4501A was present in all animals
[47]. Using the monoclonal antibodies,
cytochrome P450 1A isozymes were detected in
rat, hamster, guinea pig, rabbit, and “responsive”
mice, but not in “non-responsive” mice after
induction with MC. Similarly, isosafrole induced
cytochrome P4501A2 in all animals, but only
cytochrome P4501A1 in the rabbit and hamster
only [47].
1.1.3
Age
It has been established that the activities of
MFO are very low at birth but increase rapidly in
adult and then subsequently decline in adult in all
animal species including man [48-52]. For
example, the cytochrome P450 1A mediated 2hydroxylation of biphenyl was present in neonatal
rat and rabbit livers but this isozyme was not
detected during adulthood [53,54]. Also,
cytochrome P-450 1A1 mediated O-deethylation
of EROD was relatively higher in the neonatal rat
reaching a maximum 2 weeks after birth and then
declined with age [55]. These observations were
further confirmed since 3-week-old animals
Drug-Metabolizing Enzymes: Mechanisms and Functions
Current Drug Metabolism, 2000, Vol. 1, No. 2 109
exhibited higher EROD activity than 8-week-old
animals [56].
of a new hemoprotein, which shows maximum
absorption in its reduced carbon monoxidedifference spectrum at 448 nm (77).
1.1.4
The hepatic microsomal and nuclear
cytochromes P-450 are antigenically similar [78],
and also 3-methylcholanthrene (MC)-induces both
of them [79]. Nuclear cytochromes P-450 are
induced by many known compounds of the
microsomal cytochromes, such as pregnenalone
16α-carbonitrile (PCN), phenobarbitone (PB), βnaphthoflavone (β-NF), and the chlorinated
biphenyl mixture, Aroclor 1254 [80]. However,
the mitochondrial mixed-function oxidases differ
from the microsomal and nuclear enzymes in the
electron donor system, the mitochondrial forms
being able to operate with adrenodoxin,
ferredoxin, or the microsomal cytochrome P-450
reductase, while the microsomal and nuclear forms
function only in the presence of the reductase [81].
Despite intensive research, the induction process
itself is poorly understood and the precise
mechanisms of induction of mixed function
oxidase by xenobiotics still complex and not yet
fully elucidated.
Nutrition
Nutrition and diet may modulate the levels of
cytochrome P-450 isoenzymes, resulting in
changes in the metabolic fate of xenobiotics [5763]. The diet-mediated effects may be due to
chemicals inherent in the diet, to contaminants or
food additives, or to compounds generated during
the process of cooking [64]. Some types of food
have high contents of natural xenobiotics, which
are potent inducers of the mixed-function oxidase
system, such as saffron. Rats maintained on a diet
containing cruciferous vegetables, such as sprouts
and cabbage, probably because of their high
content of indoles, exhibited both high levels of
intestinal mixed-function oxidase activity [64].
Similar effects were observed in humans
maintained on such diet [65,66]. Indeed, indole-3acetonitrile, indole-3-carbinol, and 3,3’-diindoylmethanes present in cruciferous vegetables
have been identified as naturally occurring
inducers of hepatical and intestinal aryl
hydrocarbon hyrdoxylase [AHH], and of other
enzyme activities [67]. Liver and intestinal EROD
activities have been induced in rats by feeding
cabbage-containing diet [68].
1.1.5
Inducing Agents and Mechanism of
Induction
The administration of drugs or other
xenobiotics may lead to an increase in the
activities of various liver isozymes, which are
responsible for the metabolism of foreign
compounds [69-75]. If the increase in the activity
of a drug-metabolizing enzyme is due to an
increased level of the enzyme, then the process is
known as induction and the agent is called an
inducer (76). Inducers have been traditionally
classified either as phenobarbital (PB) or 3-methylcholanthrene (3-MC), based on the cytochrome P450 isozymes that are increased (76). Inducers of
both the PB and 3-MC type increase the total
amount of cytochromes. Although PB-treated rats
showed elevated microsomal cytochrome P-450
levels, while their synthesized hemoprotein had
the same absorption maximum in its reduced
carbon monoxide-difference spectrum at 450 nm
as microsomal cytochrome P-450 from untreated
animals (25,77). However, the biochemical and
physical changes observed after 3-MC treatment
were postulated to be due to the induced synthesis
Inducers of the cytochromes P-450 stimulate
the synthesis of new isozymes by enhancing their
rates of transcription. This mechanism appears to
be common to all cytochrome P-450 proteins but
does not extrude the presence of additional
alternative mechanism.
Nebert and his colleagues have contributed
enormously to the elucidation of the complex
process involved in the induction of the
cytochromes
P-450
[82].
The
aromatic
hydrocarbon (Ah) receptor has been demonstrated
in the hepatic cytosol of mice, which binds avidly
but noncovalently with the inducing agent which is
associated with the induction of cytochromes P450 [83,84]. This hydrophobic receptor appears to
be composed of two subunits but contains only
one binding site [85,86] and the binding appears to
involve one or more sulfhydryl groups whose
integrity is essential [87]. It appears that the parent
chemical rather than an intermediate or metabolite
that interacts with the receptor [88]. In addition to
the legend binding, a DNA-binding domain exists
on the receptor [89,90]. The inducer-receptor
complex translocated into the nucleus were
associated with structural genes leading to
increased transcription and synthesis of the Ah
receptor protein and the cytochrome P-450
apoproteins, which in the cytosol interact with
heme to form the P-450 holoenzymes [91]. A good
correlation exists between the amount of complex
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Current Drug Metabolism, 2000, Vol. 1, No. 2
translocated into the nucleus and the amount of
P450 mRNA induced [91]. Interaction of the
inducing agent with the receptor increases the
affinity of the receptor for DNA [89]. Many
endogenous compounds, including steroid
hormones, failed to interact with the receptor, and
there is considerable evidence indicating that none
of the characterized steroid receptors is similar to
the Ah receptor [92,93].
It has been suggested that inducers may affect
the initiation of protein synthesis and even
translation central factors [94]. Phenobarbitone has
been reported to increase C 14-leucine incorporation
into proteins by rat liver polyribosomes [95]. The
increased RNA and protein synthesis as well as the
stabilization and decreased degradation of these
components has been implicated in the induction
of drug metabolizing activity [96].
Induction of cytochrome P-450 is a very
complex process and may be mediated by several
processes. Manen and his coworkers (1978) have
suggested that the cyclic AMP is the intracellular
mediator of monooxygenase induction [97]. The
increased synthesis of cytochrome P-450
apoprotein produces an increased demand for
heme [98]. The mechanism of monooxygenase
induction might be also due to enhancing of deltaaminolevulinic acid (δALA) synthetase, the initial
and rate-limiting step in the biosynthesis of the
heme moiety of cytochrome P450s. It has been
reported earlier that the activity of δALA
synthetase was increased after a relatively short
period of rat treatments with some heavy metals
[99]; or may be due to inhibition of heme
oxygenase, the first and rate-limiting enzyme in
heme degradation [100], since P450s are
hemoproteins.
1.1.6
Inhibitors
It has been recognized for many years that
various chemical structures could inhibit drug
metabolism by competing for binding sites on the
mixed-function oxidase system (60, 101-103). It
has been reported that agents (e.g., lipases or
detergents) was found to alter either lipids
environment of MFO or its protein structure [4].
These agents convert the metabolically active form
of cytochrome P-450 into inactive form,
cytochrome P420. [4]. In addition, inactivation
may occur with many compounds such as carbon
disulphide [104], 2-allyl-2-isopropyl acetamide
[105] and allyl containing barbiturates [106],
heavy metals [73], which destroy cytochrome P-
Salah A. Sheweita
450 both in vivo and in vitro. Mercurials such as
mersalyl [107]; p-chloromercuribenzoate [108];
alkylating agents such as N-ethylinaleimide and
N-nitrosamines have been used as inhibitors of
many
different
metabolic
transformations
mediated by the mixed-function oxidase system
[109,110]. Bioactivation of xenobiotics by MFO is
a complex series of reactions and interference of
inhibitors with any of them may represent a
possible mechanism of inhibition [111]. Inhibitors
of cytochrome P-450 isozymes have been used as
a tool in studying the multiple forms of these
isozymes, and provide a valuable technique for
characterizing the nature of cytochrome P450.
Various disease conditions such as malignancy,
diabetes mellitus, malnutrition, schistosomal
infection, malarial infection and other infections,
can produce structural and biochemical changes in
the liver capable of decreasing the levels of
hepatic cytochrome P-450 and microsomal protein
[112-116].
Flavonoids
are
a
class
of
dietary
phytochemicals that modulate various biological
activities. Four hydroxylated flavone derivatives
(3-hydroxy-, 5-hydroxy-, 7-hydroxy-, and 3,7dihydroxy flavone) were potent inhibitors of Cyp
1A1, and 1A2 [117]. Treatment of mice with
oleanolic acid resulted in a significant decrease of
P4502E1-dependent p-nitrophenol and aniline
hydroxylase [118]. The protective effects of
oleanolic acid against the carbon tetrachlorideinduced hepatotoxicity may be due to blocking of
carbon tetrachloride bioactivation, which is
mediated by P4502E1 [118]. Trans-1, 2dichloroethylene was a more potent inhibitor of
Cyp2E1 than cis-1,2-dichloroethylene based on
both in vivo and in vitro studies [119]. In another
study, trans 1, 2-dichloroethylene yielded maximal
inactivation of P450 2E1 than other P450
isozymes including 1A2, 2A1, 2B1, 2C6, 2C11,
2D1 and 3A after 24h of treatment [120]. The
levels of hepatic P450 2B1/2, 2C11, and 3A1/2
were decreased, whereas P450 2E1 expression was
not affected after treatment of rat with acriflavine,
a protein kinase c inhibitor [121]. Moreover,
organophosphates are still widely used worldwide
and cause thousands of intoxication every year.
Repetitive exposure to subclinical doses of
parathion to rabbits for one week caused marked
inhibition of cytochrome P450 [122].
The inhibitory effects of neurotransmitters,
precursors, and metabolites on Cyp 1A2 enzyme
activity were studied in human liver microsome
[123]. Two indoleamines, serotonin and
tryptamine showed an inhibitory effect on the
Drug-Metabolizing Enzymes: Mechanisms and Functions
activity of phenacetin O-deethylase [123]. Other
substances, which were either poor or partial
inhibitors of Cyp1A2 were dopamine, L-tyrosine,
adrenaline, indole-3-acetic acid, L-tryptophan, and
5-hydroxyindole acetic acid [123].
1.2 MECHANISMS OF DRUG OXIDATION
BY MIXED-FUNCTION OXIDASE SYSTEM
The wide substrate specificity of the
microsomal mixed-function oxidases is due largely
to the multiplicity of the constitutive and inducible
cytochromes P-450, which display different, but
often overlapping substrate specificity. The mixedfunction-oxidase is primarily concerned with
detoxication involving the formation of more
polar, readily excretable metabolites [124].
Paradoxically, however, the same microsomal
mixed-function oxidase system can affect the
formation of more toxic and reactive
intermediates, a process known as "metabolic
activation or bioactivation" [125,126]. A likely
explanation of this paradox is that the activation
process may be attributed entirely to one or more
specific gene families of the cytochrome P-450
proteins, while other gene families catalyze
oxygenation which lead to detoxification. Thus the
amount of a reactive intermediate formed is the
result of these two competing processes, that is
activation and detoxication catalyzed by different
gene families of the hemoprotein [127]. As such
not only the cellular levels but also the cytochrome
P-450 isoenzyme population, will determine
whether a chemical will be activated or
deactivated and subsequently eliminated [125,126,
128,129].
It is well known that cytochrome P-450 acts as
a terminal oxidase for the electron transport
system of mixed-function oxidase, which is
implicated in the biotransformation of many
xenobiotics [130]. The two important cofactors
have been realized to be the absolute requirement
for such microsomal mediated reactions: namely,
molecular oxygen and NADPH. Absolute demand
for 0 2 was demonstrated through the incorporation
of heavy oxygen (1802) into 3,4-dimethyl phenol
[131]. Requirement of NADPH in microsomal
drug oxidation has also been demonstrated by
immunological studies with antibodies against
NADPH-cytochrome P-450 reductase [132] as
well as with purified components of the
cytochrome P-450.
Initially, a substrate binds to the apoprotein
moiety of the ferric (Fe3+) hemoprotein to form
Current Drug Metabolism, 2000, Vol. 1, No. 2 111
ferric substrate complex. This complex then
undergoes a one-electron reduction by accepting
this electron from NADPH via the flavoprotein
enzyme, NADPH cytochrome P-450 reductase,
which converts heme iron to the ferrous (Fe2+)
state. This Fe2+complex reacts with molecular
oxygen to produce an oxygenated hemoproteinsubstrate complex (02-Fe2+-substrate). The
oxycytochrome P-450 complex undergoes a
further one electron reduction. Although the origin
of the second electron is not well established,
several studies have suggested that this reduction
may be mediated via NADH-cytochrome b5
reductase and cytochrome b5 [17-19]. This
complex is then subjected to intra-molecular
rearrangement and one atom of oxygen is inserted
into substrate producing oxidized metabolites and
the other atom for water formation. Finally, the
hemoprotein product complex dissociated to give
product and free enzyme, allowing the cycle to be
repeated.
1.3 FUNCTIONS OF MIXED-FUNCTION
OXIDASE SYSTEM
There are many different forms of cytochrome
P-450 such as P-448 and 446 are present in
mammalian cells [33,46]. One of the most
important differences between the cytochromes P448 and other families of the hemoproteins, from
the point of view of chemical toxicity and disease
etiology, their is contrasting role in the metabolic
activation and detoxication of toxic chemicals and
carcinogens [79,133-135]. Cytochrome P450 1A
family almost always metabolically activates
chemicals to reactive intermediates, that is
electrophiles, which are resistant to subsequent
conjugation and interact with intracellular
macromolecules and nucleophiles, giving rise to
toxicity and carcinogenicity [126]. In contrast, the
phenobarbital-cytochromes P-450 (Cyp P-450
2B1/2) direct the overall oxidative metabolism of
chemicals toward subsequent conjugation and
detoxication. The reason for this marked
difference is that the cytochrome P-450 1A family
accepts large planar molecules, which they are
able to oxygenate in conformationally hindered
positions giving rise to epoxides and other
oxygenated metabolites that are poorly acceptable
substrates for epoxide hydrolase and other
conjugating enzymes [126]. However, the PBcytochromes P-450 generally oxygenate globular
molecules in unhindered positions to from
epoxides and other oxygenated products which are
readily acceptable substrates for epoxide hydrolase
and other conjugates, thereby resulting in
detoxication.
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Current Drug Metabolism, 2000, Vol. 1, No. 2
Salah A. Sheweita
Among the various classes of xenobiotics
known to be selectively activated by the
cytochromes P-450 1A, with the formation of
reactive intermediates, are the polycyclic aromatic
hydrocarbons (PAH), the aromatic amines and
amides, the planar polyhalogenated biphenyls and
other halogenated polycyclics, azo compounds,
mycotoxins, and paracetamol [128,129,136].
However, there are a few known instances where
PB-induction increases chemical toxicity, or the
PB-cytochromes P-450 specifically metabolize
chemicals via toxic pathways, and these include
the activation of cyclophosphamide, and the
toxicity
of
bromobenzene
and
carbon
tetrachloride.
Britain was associated with the occupation of
patients as chimney sweeps [143]. Since that time,
people in other occupations have been
demonstrated to have certain risk of developing
cancer at some sites. Overall, however,
occupational cancers are relatively rare events that
affect only limited numbers of individuals. The
bulk of human cancers were until recently
considered to stem from unknown elements. It was
primarily the examination of international
incidence rates of various types of cancer, and the
fact that the incidence depends in part on the site
of residence, that led to the concept that many
types of human cancer are caused, mediated, or
modified by environmental factors [144-147].
1.3.1
Chemical carcinogens are defined operationally
by their ability to induce tumors. Four types of
response have generally been accepted as evidence
of tumorigenicity: (1) an increased incidence of
the tumor types occurring in controls; (2) the
occurrence of tumors earlier than in controls; (3)
the development of types of tumors not seen in
controls; (4) an increased multiplicity of tumors in
individual animals. Chemicals capable of eliciting
one of these tumorigenic responses are thereby
classified as carcinogens. They comprise a highly
diverse collection, including organic and inorganic
chemicals, solid-state materials, hormones, and
immunosuppressants. In order to draw attention to
the differences in properties of the diverse agents
that can be considered as carcinogenic,
Weisburger and Williams have developed a
classification based on the mechanistic mode of
action of carcinogen [146], which separate them
into eight classes. These in turn can be divided
into two general categories based on their ability
to damage DNA [146]. Carcinogens that undergo
covalent reactions with DNA are categorized as
genotoxic, and those lacking this property are
designated as epigenetic, the eight classes have
been divided between these two categories [147].
The genotoxic category contains those agents that
function as electrophilic reactants, a property of
carcinogens originally postulated by Miller and
Miller in 1976 [148]. In addition, carcinogenic
chemicals that give rise to DNA damage through
formation of free radicals derived from their own
molecular structure or from altered cellular
macromolecules, would be considered genotoxic.
The second broad category, designated as
epigenetic
carcinogens,
comprises
those
carcinogens for which no evidence of direct
interaction with material exists or DNA [148].
Within this broad definition of carcinogens, many
structural types of chemicals are included such as
those in the class of the direct acting carcinogens
Metabolism of Endogenous Substrates
The cytochromes P-450 2C11 catalyze specific
steroid hydroxylation from livers of both rats and
rabbits [17,49,137-139]. The PB-cytochromes P450 and cytochromes P-450 1A can hydroxylate
steroids, but generally do so at rates well below
those occurring in crude microsomes, indicating
that steroids are unlikely to be the primary
endogenous substrates of these cytochromes.
However, even in the hydroxylation of steroids,
PB-cytochromes P-450 and MC-cytochromes P448 again show distinct differences in region
selectivity with virtually no overlap [139]. In the
2-hydroxylation of 17β-estradiol, cytochrome
P4501A2 is markedly more active than any other
cytochrome P-450 protein [140]. Differences in
the sites of oxygenations by the MC-cytochromes
P-448 and PB-cytochromes P-450 are also seen
with the endogenous substrate arachidonic acid
[30]. Cytochrome P-448 proteins from livers of
rats and rabbits pretreated with β-naphtoflavone
(β-NF) formed primarily ω- and (ω-1)hydroxylated products, while, in contrast,
preparations from animals pretreated with PB gave
primarily four epoxides [141,142]. A cytochrome
P-450 protein catalyzing the epoxidation of
arachidonic acid has been isolated from human
liver [142]. Interestingly, this protein had high
catalytic activity toward 7-ethoxyresorufin and it
might be related to cytochromes P-450 1A family
[142].
1.3.2
Metabolic
Carcinogens
Activation
of
Chemical
The concept that some types of cancer might be
caused by environmental factors traces back to the
observation of the English physician Pott in the
late 18th century that human scrotal cancer in Great
Drug-Metabolizing Enzymes: Mechanisms and Functions
[146-148]. They do not require the participation of
enzymes from the host organism to generate the
key reactive intermediate of the ultimate
carcinogens. However, they do not generally
persist in the environment because of their high
reactivity.
The second class of genotoxic carcinogens,
termed procarcinogens, is comprised of organic
chemicals that are active only after metabolic
conversion by the host. This class include most of
the known chemical carcinogens, and in contrast
to direct-acting carcinogens can exist in the
environment in a relatively stable condition until
taken in by an exposed individual and activated
through biotransformation [147,148].
1.3.2.1 Polycyclic Aromatic Hydrocarbons
Polycyclic
aromatic
hydrocarbons
are
ubiquitous in the environment and some of them
are believed to cause cancer in man [149-151].
Benzo[a]pyrene is present as a component of the
total content of polynuclear aromatic compounds
in the environment. Human exposure to
benzo[a]pyrene occurs primarily through the
smoking of tobacco, inhalation of polluted air and
by ingestion of food and water contaminated by
combustion effluents [145]. Benzo [a] pyrene has
been shown to be carcinogenic to experimental
animals [153-158]. It has produced tumors in all of
animal species following different administrations
including oral, skin and intratracheal routes. It has
both a local and a systemic carcinogenic effect. In
sub-human primates, there is convincing evidence
of the ability of benzo(a)pyrene to produce local
sarcomas following repeated subcutaneous
injections and lung carcinomas following
intratracheal instillation. It is also an initiator of
skin carcinogenesis in mice, and it is carcinogenic
in single-dose experiments and following prenatal
exposure [159].
Polycyclic aromatic hydrocarbons (PAH) not
only induce the cytochromes P-448 but also are
preferentially metabolized by these enzymes. The
cytochrome P450 system participates in the
bioactivation of polycyclic aromatic hydrocarbons
(PAHs) and other carcinogens to their reactive
intermediates [160-163]. An important and very
extensively studied member of the polycyclic
aromatic hydrocarbons is benzo(a)pyrene which is
mainly metabolized by cytochrome P450dependent aryl hydrocarbon hydroxylase into
various derivatives, among which are electrophilic
epoxides
[147,157].
Solublized,
purified
Cytochrome P450 2A1 preparations were more
efficient than the PB-cytochromes P-450 in
Current Drug Metabolism, 2000, Vol. 1, No. 2 113
converting
benzo(a)pyrene
and
(±)-transbenzo(a)pyrene -7,8-dihydrodiol, the precursor of
the ultimate carcinogen, into mutagens [29,68].
Similarly hepatic microsomal preparations form
MC-treated animals are markedly more efficient
than similar preparations from PB-induced animals
in activating benzo(a)pyrene to mutagens and in
converting it to the 7,8-diol-9,10-epoxide [38].
Pretreatment of rats with PB increased the
formation of the 4,5-diol of benzo(a)pyrene but
had little or no effect on the 7,8-and 9,10-diol
formation; the formation of all three diols was,
however, induced by pretreatment with β-NF and
MC, the least effect being seen with the 4,5 diol
[161]. The MC-induced type increased in benzo
(a) pyrene mutagenesis [160,164]. Intraperitoneal
pretreatment of mice with MC increased the
formation of benzo(a)pyrene 7,8-diol in both lung
and liver, while no such effect was seen following
treatment with phenobarbital [159]. Furthermore,
pretreatment of mice by intratracheal instillation of
benzo(a)pyrene increased markedly the covalent
binding of the carcinogen to lung DNA [165].
Supporting these findings are immunological
studies which showed that the metabolic activation
of benzo(a)pyrene to mutagens was markedly
inhibited by antibodies to cytochrome P4501A1
but was unaffected by antibodies against
cytochrome P-450 2E1 [166]. Similarly, a
monoclonal antibody against MC induced
cytochromes P-448 inhibited the conversion of
benzo(a) pyrene 7,8 diol to mutagens by liver
microsomes from MC-induced responsive mice
while no effect was seen with an antibody to PBinduced microsomes [167]. Finally, good
correlation has been obtained between rat liver
cytochrome P450 1A content determined by the
ethoxyresourfin O-deethylase (EROD) assay and
the activation of benzo(a)pyrene to mutagens in
the Ames test by rat liver microsomes [167]. The
alcohol-inducible cytochrome P-450 isoenzymes
(P450 2 E1) appear not to catalyze the activation
of PAH [168]. The carcinogenic potency and the
extent of binding of these metabolites, epoxides,
with DNA and proteins are correlated with the
induction of cytochrome P-450-dependent aryl
hydrocarbon hydroxylase activity [169,170]. The
preferential activation of PAH by cytochromes P448 is not confined to benzo(a)pyrene.
Cytochromes P-448 also convert MC, 6aminochrysene, benzo(a)anthracene, dibenzo(a,h)
anthracene, dibenze(a,c) anthracene, and many
other bay-region-containing PAH to highly
mutagenic species [166,171,172].
114
Current Drug Metabolism, 2000, Vol. 1, No. 2
1.3.2.2 Naturally
Occurring
Carcinogen
(Aflatoxin B1)
Until the early 1950s it was thought that
virtually all-organic chemicals were man-made.
However, in the beginning of 1955 it was
increasingly realized that some chemical
compounds elaborated by certain plants are
carcinogenic. The demonstration in the early
1960s of the potent carcinogenicity of aflatoxins
revealed that carcinogens are also found among
metabolites of certain molds and microorganisms
[173]. Thus, nature itself contributes a fair share to
the cancer causing substances in the environment,
the naturally occurring carcinogen [173].
Aflatoxins were discovered in England in 1960
when a Brazilian peanut meal was used as a
protein supplement to poultry diets caused the
acute deaths of more than 100,000 young turkeys
from liver damage or turkey X disease [174]. At
the same time, an outbreak of turkey X like
disease in ducklings occurred in Kenya following
the ingestion of African peanut meal [175].
Symptoms similar to turkey X disease were also
reported in outbreaks in other form or domestic
animals fed peanut meals. Coincidentally, an
epizootic of liver cancer in hatchery-reared
rainbow trout occurred in the United States and
Europe in 1960 [176-178]. A commercial trout
feed contaminated cottonseed meal was eventually
found to be associated with the trout hepatoma
problem. The magnitude of the problem inspired
intensive research efforts by investigators
throughout the world [179]. The toxic agent in
peanut meal was narrowed down to a mixture of
aflatoxins produced by a common mold,
Aspergillus flavus, as secondary metabolites [175].
The mixture could be separated into four
components by thin layer chromatography; these
were designated BI, B2, G1, and G2 according to
their fluorescent colors (B1 for blue, G1 for green)
and relative mobility in the chromatogram
[180,181].
1.3.2.2.1
Metabolism and Mechanism of
Action of Aflatoxin B1
Aflatoxin B1 is actively metabolized in a variety
of animal species. Epoxidation of the 2,3 double
bond of AFB1 is now generally accepted to be the
key metabolic reaction eliciting the carcinogenic
and mutagenic effects of the mycotoxin [182].
That the 2,3-double bond is a critical structural
requirement for carcinogenicity and mutagenicity
has been pinpointed by structure-activity
relationship studies on a variety of structural
analogs of AFB1 [183,184]. Moreover, quantum
mechanical calculations have shown that the 2,3-
Salah A. Sheweita
double bond is the most reactive site in the
molecule [185,186]. Although attempts to isolate
the putative reactive intermediate, AFB1-2, 3oxide, have been unsuccessful because of
instability, its formation can be deduced from its
reaction products with cellular constituents and its
hydrolysis products. Aflatoxin B1 binds covalently
to nucleic acids after in vitro metabolic activation
by liver microsomes [182,187-189] as well as in
vivo studies [183,190]. The major acid hydrolysis
products of AFB1-DNA adducts were identified as
2,3-dihydro-2- (N7-guanyl)-3-hydroxyaflatoxin B1
and 2,3-dihydro-2- (2,6-diamino-4-oxo-3, 4dihydro-pyrimid -5-ylformamido)-3-hydroxy aflatoxin B1 indicating the involvement of AFB1-2, 3oxide [189]. In the absence of exogenous
nucleophiles, 2,3-dihydro-2,3-dihydroxy-aflatoxin
B1, an expected hydrolysis product of AFB1-2,3oxide, is a major metabolite in the incubation of
AFB1 with rat, hamster, and trout liver microsomes
[184,191,192]. The relative importance of each
individual pathway varies substantially, depending
on the animal species and the experimental
conditions. Essentially, the initial metabolism of
AFB1 involves three principal types of reactions:
(a) hydroxylation, (b) epoxidation, and (c) keto
reduction. The former two reactions believed to be
carried out principally by a microsomal mixedfunction oxidase system, the latter by a cytosolic
NADPH-dependent reductase. In most animal
species, the hydroxylated AFB1 metabolites may
undergo phase II metabolism by conjugating with
gulcuronic acid or sulfate [193]. The activation of
this mycotoxin to mutagenic and carcinogenic
products, involving epoxidation of the 2,3-double
bond and possibly other oxygenation, appears to
be catalyzed by the cytochromes P-448 and
possibly other forms of the cytochromes
[184,194]. A comparison of 5 purified rat
cytochrome P-450 proteins in the activation of
aflatoxin B1 into mutagens showed that
cytochrome P4501A2 and a sex-related male form
were the best efficient. Although a significant
activity was also seen with cytochromes P-450
1A1 and P-4501A2 [195], other workers who
further showed that although PB-uninducable
forms have activated this mycotoxin, have
documented the high efficiency of cytochrome
P450 3A4 [196]. The hepatic microsomal enzyme
system that catalyzes the 2,3-epoxidation of AFB1
exhibits the typical characteristics of a mixedfunction oxidase. Pretreatment of animals with
Phenobarbital (but not with 3-methylcholanthrene)
greatly enhances the in vitro formation of adducts
of AFB1 with nucleic acids, suggesting the
involvement of a cytochrome P-450-dependent
system. However, somewhat inconsistent results
Drug-Metabolizing Enzymes: Mechanisms and Functions
have been obtained from reconstitution experiments using purified cytochromes. In two of these
studies purified hepatic cytochrome P450 1A
species obtained from polychlorinated biphenyl- or
3-methylcholanthrene-treated rats were more
effective than purified Phenobarbital-induced
cytochrome P-450 2B1/2 in catalyzing the
formation of a reactive intermediate that binds to
DNA or exerts a mutagenic effect [195,196]. In a
third study, purified Phenobarbital-induced rat
liver cytochrome P-450 was more active than βnaphthoflavone-induced cytochrome P450 3A4 in
catalyzing the formation of AFB1-DNA adduct
[197-199].
1.3.2.3
N-Nitrosamines
N-nitrosoamines are an important class of
environmental carcinogens, and their potential role
as causative agents in the carcinogenesis of some
human neoplastic diseases has been extensively
reviewed [200-206]. There are two potential
sources of human exposure to nitrosamines.
Firstly, certain dietary items are known to contain
nitrosoamines [207]. Secondly, A more important
source of nitrosamines is almost certainly from
ingested amines and nitrite. The nitrite can come
from foods containing nitrite, such as cured meat
and fish, or be present in saliva and enter the
stomach in that way. Nitrosotable amines can be of
enormous variety. A majority of drugs and
medicines are nitrosotable amines; many
agricultural chemicals are nitrosotable amino
compounds, and many constituents of food
themselves, as well as food additives, are amines of
this type [208-212]. The amino acid proline is one
example of naturally occurring nitrosotable
amines, although it gives rise to a noncarcinogenic nitroso derivative. More recent
studies have shown that the urinary levels of
nitrosamines are higher in Egyptian schistosomal
patients than those of the controls [213,214].
1.3.2.3.1
Bioactivatlon
of
N-nitroso
Compounds
N-nitrosourea
and
related
compounds
(nitrosoamides, nitrosoguanidine, nitrosourethans,
nitrosocyanamides ) are chemically reactive, and
decompose at physiological pH to form
electrophilic alkylating agents. N-nitrosamines, on
the other hand, are stable at neutral pH, and
require metabolic transformation in vivo in order
to exert their carcinogenic effects [215-220]. This
difference explains why nitrosourea tend to
produce tumors at or near the site of application,
Current Drug Metabolism, 2000, Vol. 1, No. 2 115
whereas nitrosamines produce tumors in tissues
remote from the site of administration.
Nitrosamines are potent carcinogens for a
variety of animal species and metabolic activation
is known to be required for their carcinogenecity.
Dimethylnitrosamine (DMN) has been used
frequently as a prototype compound in studying
the metabolism of nitrosamines [217]. It is known
that the metabolism of DMN can be mediated by a
liver microsomal fraction which requires NADPH
and molecular oxygen. There are two enzyme
species responsible for the N-demethylation of
dimethylnitrosamine (DMN) through an oxidative
N-demethylation reaction, namely DMN-Ndemethylases I and II (which can operate at ~ 4
mM and ~200 mM of DMN respectively)
[69,221]. It was found that following the Ndemethylation of dimethylnitrosamine (DMN), a
diazonium ion is produced leading ultimately to
the formation of carbonium ion that methylates
DNA [222-224]. It was suggested that the
carcinogenic effects of alkylating agents are
proportional to the activities of their activating
enzymes in the liver [225,226] since more of the
active metabolites might be produced [226], when
the demethylases are activated. Therefore, the
carcinogenic effects of carbonium ion resulting
from activation of N-nitrosodimethylamine might
be increased toward the liver and probably other
organs. It has, therefore been postulated that the
reaction involves oxidative demethylation to
eliminate formaldehyde, which has been identified
as a product, and carbonium ion, which alkylates
accessible nucleophiles, including nucleic acids,
proteins and water.
1.3.2.3.2
Role of Cytochrome P450 2E1 in the
Activation of N-Nitrosamines
Among six purified human cytochrome P450
forms, the alcohol-induced P450 2E1 was the most
efficient in catalyzing the demethylation and
denitrosation of dimethylntrosamine (DMN) [227231]. Moreover studies with purified rat liver P450
isozymes demonstrated that Cyp2E1 is more
active than other forms in catalyzing the
metabolism of dimethylnitrosamine [231,232].
Other P450 forms such as phenobarbital-inducible
P450b showed substantial activities only at high
substrate concentrations of dimethylnitrosamine,
suggesting high Km values [69,231,233]. These
observations are consistent with the concept that
the multiple Km values for dimethylnitrosamine
N-demethylase found in microsomes are due to the
catalytic activity of multiple forms of P450 [229].
116
Current Drug Metabolism, 2000, Vol. 1, No. 2
The key role of dimethylnitrosamine Ndemethylase in the activation of dimethylnitrosamine has been demonstrated in several
different system: [1] cytochrome P450 2E1 was
more efficient than other forms in the activation of
dimethylnitrosamine to a mutagen in Chinese
hamster [233]; [2] some of the previously reported
species and age difference in DMN have been
interpreted on the basis of the quantity of P450
2E1 present in the hepatic microsomes of rats and
hamasters of different age [234]; and [3]
pretreatment of rats with ethanol or acetone
increased DMN-induced methylation of DNA in
vivo and in vitro and potentiated hepatotoxicity
[235,236].
The ultimate effect of N-nitrosamines will
depend upon the rate of activation and the rate of
detoxification. As the activated carcinogen reacts
with various nucleophilic sites in addition to
nucleic acids) and as water is the most plentiful
cellular component, reaction with water could be
regarded as detoxifying process [237]. Similarly,
the trapping of reactive intermediates by protein
and other cellular components also provides
protection against the mutagenic and carcinogenic
effects of N-nitrosamines although not against
some of the cytotoxic effects of these agents [237].
In addition, there are other mechanisms of
metabolic detoxification of N-nitrosamines by
glutathione S-transferases [238], all of which limit
the formation of the highly reactive electrophilic
intermediates. Although trapping of reactive
metabolites by glutathione conjugation appears to
be the primary defense mechanism against the
harmful effects of reactive intermediates, in some
cases the conjugation of an ultimate carcinogen
with glutathione can form genotoxic species [239].
The electrophilic intermediates produced by
chemical decomposition of nitrosourea and related
compounds, or by metabolic activation of
nitrosamines, react rapidly with cellular
nucleophiles. Attention has been focused on
reactions with DNA because this is generally
considered to be the critical cellular target for
carcinogens during tumor initiation [223,240].
Although 7-methylguanine (66.8 %) is the most
abundant modified base in DNA produced by
dimethy-lnitrosamine, a variety of other products
have been identified [216,217,240]. These include
alkylphosphate triesters (12 %), 1-,3- and 7methyladenine ( 0.9 %, 2.3%, 0.7%); and 06methylguanine (6.1%) and unidentified products.
Not all DNA lesions have the same biological
importance [223,240]. Methylation of the 7position of guanine shows no correlation with
Salah A. Sheweita
carcinogenic activity, but several striking
correlation have been obtained between tissue
susceptibility to tumor induction and the initial
extent of formation and subsequent persistence of
06-methyl guanine residue [223,240].
1.3.2.4
Aromatic Amines and Amides
The aromatic amines include some very
important
industrial
chemicals
used
as
intermediates in the manufacture of dyes and
pigments for textile, paints, plastics, paper and hair
dyes; they also include drugs, pesticides and
antioxidants used in the preparation of rubber for
the manufacture of tires and cables [241,242].
Studies of bladder cancer among workers in the
dyestuff industry and later among rubber workers
hold an important place in the history of
occupational bladder cancer. Epidemiological
studies of the hazards to workers in the chemical
industry established that benzidine and 2naphthylamine are carcinogenic to humans
[241,242]. It was shown that rubber workers also
had increased risk for bladder cancer, attributed
largely to exposure to aromatic amines [241,242].
Most aromatic amines are initially activated by Nhydroxylation, mainly in the liver via a
cytochrome P-450 catalyzed reaction [243,244].
Studies of bladder cancer among workers in the
dyestuffs industry, and later among rubber
workers, hold an important place in the history of
"occupational" bladder cancer. This evidence led
to the International Labor Organization to declare
certain aromatic amines as human carcinogen
[245]. The epidemiological study for the hazards
on workers in the chemical industry, established
that benzidine and 2-naphthylamine were
carcinogenic to human [245,246]. In another study
carried out at about the same time, it was shown
that rubber workers had also an increased risk for
bladder cancer, attributed largely to exposure to
aromatic amines. 4-aminobiphenyl was widely
used in the industry at that time, and it was shown
shortly afterwards that it caused bladder cancer in
humans [246,247]. The epidemiological finding
subsequently prompted discontinuation of
production and prevented widespread use of 4aminobiphenyl in other countries. Recent
epidemiological studies have demonstrated an
elevated occurrence of bladder cancer among
workers exposed to para-chloro-ortho-toluidine.
Since it also induced malignant tumors in
experimental animals, this compound and its
strong acid salts are probably carcinogenic to
human [248].
Drug-Metabolizing Enzymes: Mechanisms and Functions
1.3.2.4.1
Metabolic
Activation
of
2Acetylaminofluorene
Activation of 2-acetylaminofluorene (2-AAF)
proceeds through N-hydroxylation which is
catalyzed exclusively by cytochromes P-448 [249251], confirming previous observations where
antibodies to cytochromes P-448, but not PBcytochromes
P-450,
decreased
the
Nhydroxylation and covalent binding of the
carcinogen [252-254]. Pretreatment of animals
with 2-AAF or MC increases the N-hydroxylation
of the amide, and increases the cytochromes P-448
content as determined by EROD activity
[255,256]. Similarly, rabbit liver microsomes
catalyze the N-hydroxylation of 2-AAF.
Furthermore, monoclonal antibodies to MCinduced cytochromes P-448 inhibited the Nhydroxylation of 2-AAF [257], and the
mutagenicity of 2-AAF was inhibited 60% by
antibodies to cytochrome P450 3A4 but only 35%
by antibodies to cytochrome P-450. Nhydroxylation of acetylaminofluorene occurs to
the greatest extent in the liver and is catalyzed by a
cytochrome P-450 and NADPH-generating system
in the endoplasmic reticulum [251,258]. A major
fraction of N-hydroxy-AFF is converted to its 0glucuronide, which is excreted in the bile and
urine [259,260,261]. This glucuronide has weak
electrophilic reactivity, but its N-deacetylated
derivative is a potent electrophile, although the
latter compound is not a known metabolite [262].
Male Sprague-Dawley rats and male and female
rats of the Fisher strain, all of which are highly
susceptible to hepatic tumor induction, have a high
level of cytosolic 3'-phosphoadenosine-5'phosphosulfate (PAPS)-mediated sulfotransferase
activity for N-hydroxy-AAF in their livers [263266]. The activity of sulfotransferases in liver
cytosol under various experimental conditions
correlates with the extent of covalent binding of
several of amines and amides to macromolecules
and with susceptibility of animals to the
hepatocarcinogenicity of N-hydroxy-AAF. Thus,
the sulfuric acid ester appears to be the major
ultimate carcinogenic metabolite of N-hydroxyAFF in the liver [267,268].
N, 0-acyltransferase, which catalyses the
transfer of the N-acetyl group of N-hydroxy-AAF
to the oxygen atom of the corresponding
hydroxyamine (formed by N-deacetylation),
occurs in a wide variety of tissues in rat and other
species [269,270]. The 0-acetyl derivative of Nhydroxy-2-aminofluorene is a very strong
electrophile. Because of the wide tissue
distribution of N, 0-acyltransferase, this metabolic
pathway is an alternative mechanism for the
Current Drug Metabolism, 2000, Vol. 1, No. 2 117
metabolic activation of N-hydroxy-AAF or other
hydroxamic acids in tissues. Since arylaminated
residues are major products found in rat liver DNA
following administration of N-hydroxy-AAF this
acyltransferase may also play a role in the
formation of 2-aminofluorene moieties which
become attached to DNA [271,272]
The major hepatic nucleic acid adducts in rat
liver from N-hydroxy-AFF-treated animals are N2-(guan-8-yl)-AAF or aminofluorene derivatives.
In addition, 3-(guan-N2-yl)-AFF has been
identified in hepatic DNA. The latter modified
base persists much longer in DNA than the first
adduct [253,273].
1.3.2.4.2
Metabolic Activation of N,NDimethylaminoazobenzene
The N-hydroxylation of N-methylaminoazobenzene and the metabolic activation of N, Ndimethylaminoazobezene are catalyzed by
cytochromes P-448 [274,275]; cytochrome
P4501A2 catalyzes the N-hydroxylation of Nmethylaminoazobenzene at twice the rate of
cytochrome P4501A1 although the latter is more
active in ring hydroxylation [26,27,68]. N-methyl4-aminoazobenzene (MAB) is a proximate
carcinogenic metabolite formed from N, Ndimethylaminoazobenzene through oxidative Ndemethylation. This hepatocarcinogen is then Nhydroxylated by a flavoprotein that requires
NADPH, but not cytochrome P-450 [277].
Carcinogenicity studies in rats and mice led to the
conclusion that N-hydroxy metabolites of MAB
and other amino azo dyes are proximate
carcinogens [278]. N-hydroxy-MAB is esterified
by a PAPS-dependent cytosolic system in rat liver
[279]; this ester is presumed to be the ultimate
carcinogenic
metabolite.
Livers
of
rats
administered MAB in vivo contained the same
nucleic acid and protein-bound adducts that are
formed on incubation of the synthetic benzoic acid
ester of N-hydroxy-MAB with nucleophiles in
vitro [280]; the nucleic acid adducts are N-(guan8-yl)-MAB derivatives [280]. Protein-bound
cysteine derivatives are formed in vivo and these
amino acid adducts have been characterized. The
susceptibilities of the livers of the rat and several
rodent species correlate with the capacities of
these tissues to form N-hydroxy-MAB and the
sulfate ester of this product [277,279]. Thus the
addition of sulfate ester to the diet of rats enhances
the induction of liver tumors by the related amino
azo dye, 3'-methyl-N,N-dimethyl-4-aminoazobenzene [281].
118
Current Drug Metabolism, 2000, Vol. 1, No. 2
The cleavage of azo bonds, catalyzed by the
enzyme azo reductase, may lead to detoxification
of certain carcinogenic and mutagenic azo dyes,
such as N,N-dimethyaminoazobenzene. In other
instances, such a reaction may activate azo
compound [282].
1.4 ENZYMES
INACTIVATION
OF
CARCINOGEN
1.4.1
Glutathione and other Amino Acids
Conjugation
Glutathione (GSH) is present in most plant and
animal tissues from which the human diet is
derived. GSH can function as an antioxidant,
maintain ascorbate in a reduced and functional
form, directly react with and inactivate toxic
electrophiles in the diet, and can be broken down
to yield cysteine [283]. Studies have shown that
dietary GSH enhances metabolic clearance of
dietary peroxidized lipids and decreases their net
absorption [284] and that consumption of food
high in GSH content is associated with about a
50% reduction in risk of oral and pharyngeal
cancer [285]. Therefore, an improved understanding of the distribution of GSH in foods and
the factors affecting GSH absorption and
distribution can be expected to provide the basis
for improved food selection and preparation to
reduce risk of chronic diseases.
Glutathione (GSH) one of the most abundant
intracellular thiols, aids in the protection of cells
from the lethal effects of toxic and carcinogenic
compounds [286,287]. It has shown to be an
important determinant of cellular sensitivity to a
wide variety of drugs and other cytotoxic
compounds [288-290]. Both oxidation-reduction
reactions may eventually result in GSH depletion
even though the former type of reaction primarily
leads to glutathione oxidation and should be
effectively compensated by glutathione reductase
activity [291]. GSH depletion is often associated
with cytotoxicity, and there are some indications
that conjugation reactions can be more detrimental
to the cell than redox cycles [292, 293]. It thus
seems possible that GSH depletion may promote
tumor development through a mechanism that
involves cytotoxicity and other different ways
[294, 295]. The cytosolic glutathione-S-transferase
and GSH play an important role in the
detoxification of many environmental chemicals
including mutagens and carcinogens [296-300].
Their main function is the conjugation of GSH to a
variety of electrophilic compounds. Recent studies
have demonstrated that GSH and GST reduced the
Salah A. Sheweita
covalent binding of epoxides of well known
chemical carcinogens, e.g. aflatoxin B1 and benzo
[a]pyrene, with DNA [301-305]. It has been
reported that such DNA-binding was found to be
effective in decreasing the hepatocarcinogenesis
caused by these compounds [306,307].
Glutathione conjugates are not excreted per se
but rather undergo further enzymatic modification
of the peptide moiety resulting in the urinary or
biliary excretion of cysteinyl-sulfur substituted, nacylcysteines, more commonly referred to
mercapturic acids [295]. Mercapturic acid
formation is initiated by glutathionase conjugation
followed by removal of the glutamate moiety by
glutathionase and subsequent removal of glycine
by a peptidase enzyme, the latter two enzymes
being present in both liver, gastrointestinal tract
and kidney. In the final step, the amino group of
cysteine is acetylated by a hepatic n-acetylase
resulting in formation of the mercapturic acid
derivative. This latter acetylation reaction is
reversible and deacetylases can reform the amino
metabolite [308].
It is clear that glutathione conjugation serves as
a protective mechanism whereby potentially toxic,
electrophilic metabolites, are detoxified either as
glutathione conjugates or mercapturic acids [306308]. However, it is becoming increasingly
recognized that glutathione conjugation is not
exclusively a detoxification reaction and that
certain xenobiotics are toxicologically activated by
this conjugation route, either as such or as a result
of further processing of the glutathione conjugate.
Therefore, cellular levels of glutathione are an
important determinant of xenobiotic toxicity
[292,293,307].
The covalent binding of electrophilic
metabolites to DNA has been extensively studied
as primary mechanism of triggering mutagenic or
carcinogenic events. Some studies have
successfully identified the target amino acids to
which drug metabolites bind during the covalent
interactions with proteins. In general, the most
reactive target sites in proteins include the
nucleophilic centers of cysteine, methionine,
histidine and tyrosine [309]. Thiol sulfur
represents a particularly potent nucleophilic site in
a protein. Ample evidence suggests that protein
sulfhydryl groups may be important sites for attack
by electrophilic drug metabolites resulting in
covalent binding. Sulfhydryl blocking agents often
decreases the covalent binding of drug to protein
thiols [310,311]. Exposure of Chinese hamster to
potassium chromate leads to the formation of
Drug-Metabolizing Enzymes: Mechanisms and Functions
stable complexes between DNA and amino acids
([312]. Cysteine, glutamic acid, and histidine were
the major amino acids crosslinked to DNA in
chromate-treated hamster [312]
1.4.2
Glutathione-S-Transferase (GST)
The glutathione-S-transferase enzymes are
soluble proteins predominantly found in the
cytosol of hepatocytes and catalyze the
conjugation of a variety of compounds with the
endogenous tripeptide, glutathione. Cytosolic
glutathione S-transferases can be divided into four
families, termed alph (α), mu (µ), Pi(π), and theta
(φ), having different but sometimes overlapping
substrate
specificities
[298,302,313-315].
Glutathione S-transferases are subjected to
activation by endogenous disulfides and by
various intermediates that form during the
metabolism of drugs and other foreign compounds
[316]. Individual variation in the expression of
GST isozymes is well documented [317]. For
example, the levels of GSTα class isozymes can
vary markedly between individuals [318], and in
the case of GSTµ class, as a consequence of
genetic polymorphism, about 45% of individuals
do not express GSTµ subunits [319]. Such
variation in expression of GST isozymes may
predispose individuals to the toxic effects of
environmental carcinogens. A number of studies
demonstrating that high levels of GSTπ in
neoplastic nodules in several rat models of
hepatocarcinogenesis have prompted investigations of GSTπ levels in human tumors. The
predominant form in most human tumors
investigated was class GSTπ and comparison of
matched pairs of normal and tumor tissues
revealed high levels in stomach, colon, bladder,
cervix and lung tumors [320-323]. GSTπ serves as
a marker for hepatotoxicity in rodent system [324],
and also plays an important role in carcinogen
detoxification. Therefore, inhibition of GST
activity and depletion of GSH levels might
potentiate the deleterious effects of many
environmental
toxicants
and
carcinogens.
Glutathione-S-transferases (GSTs) have the
capacity to detoxify electrophilic xenobiotics by
catalyzing the formation of glutathione (GSH)
conjugates. GSTs are also engaged in the
intracellular transport of variety of hormones,
endogenous metabolites, and drugs, by virtue of
their capacity to bind these substances [325]. A
series of carcinogens drugs, metabolites, and
related compounds were analyzed for binding to
GST [326]. Broad specificity of binding is evident,
but relative affinities are not determined by
Current Drug Metabolism, 2000, Vol. 1, No. 2 119
lipophilicity alone. This is exemplified by the
striking
differences
between
2,3-benzo(a)
anthracene, which was bound with high affinity,
and 1,2-benzo(a)anthracene, which was classified
as non-binding. Distinct structural requirements
emerged from these results [326]. Steric factors
appear to dictate binding; the polysubstituted
anthracenes such as the dibenzanthracenes, pyrene,
chrysene and other polycyclic aromatic
compounds were bound. Similarly, dibenz(a,j)
acridine was bound whereas acridine and acridine
orange were not bound [306]. It is well known that
parasites and heavy metals caused marked changes
in GST activity, and GSH levels [327-329].
Inducers of GSTs are generally considered as
protective compounds against cancer, acting as
blocking agents. The human diet contains many
compounds that inhibit various steps of the
carcinogenic process [330]. The coffee specific
diterpenses cafestol and kahweol have been
reported to be anti-carcinogenic in several animal
models. It has been postulated that this activity
may be related to their ability to the induction of
glutathione S-transferase π class [331]. GSTπ was
induced in the stomach by coumarin and αangelicalactone and in the pancrease by flavone
[332]. Several dietary compounds have been
demonstrated to reduce gastrointestinal cancer
rates in both human and animals. For example,
sulforaphane, indole-3-carbinol, D-limonene and
relafen induced GSTα levels in small intestine and
livers, GSTµ levels in stomach and small intestine,
GSTπ levels in stomach and small and large
intestine [333]. Aqueous extracts of either green or
black tea were administered to rats as the sole
drinking fluid for 4 weeks. Hepatic GST activity
and UDP-Glucuronyl transferase were induced
[333].
On the other hand, many different chemical
compounds and dietary items were found to inhibit
the expression and the activity of GST isozymes.
Trivalent antimony was a potent inhibitor of
glutathione
S-transferases
from
human
erythrocytes [335]. Based on this inhibition
characteristics and the preferential accumulation of
trivalent antimony in mammalian erythrocytes, for
example, during therapeutic treatment of
Leishmaniasis, antimony levels in erythrocytes
may be high enough to depress GST activity,
which might compromise the ability of
erythrocytes to detoxify electrophilic xenobiotics
[335]. Animals treated with acriflavine, a protein
kinase c inhibitor, and allyl disulfide showed
complete blockage of GST gene expression as
early as 12 h of treatment [299]. Analogues of
120
Current Drug Metabolism, 2000, Vol. 1, No. 2
glutathione preferentially inhibit GSTα, have less
effect on µ isozymes, and finally have little effect
on rat φ and π isozymes [336-338].
1.4.3
Glutathione Reductase
Glutathione reductase from several tissue
sources has been extensively characterized. Its
catalytic mechanism, amino acid sequence and its
three dimensional crystal structure have been
determined [339,340]. But little is known about
the physiological regulation of its activity. The
role of glutathione reductase is to maintain the
cellular level of reduced glutathione. Its substrates
and/or products in vivo do not regulate glutathione
reductase activity. However, there have been
several reports hinting at the in vivo inhibition of
the enzyme by GSH. No details of the inhibition
were provided in these early reports [341,342].
The first such detailed report on the inhibition of
glutathione reductase by GSH appeared in the
literature [343]. In that study, GSH was shown to
be a non-linear, non-competitive inhibitor of
glutathione reductase [343]. The inhibition of
glutathione reductase by GSH appear to be a wide
spread phenomenon that should hereafter be
considered in any treatment of GSH metabolism or
homeostasis on the enzymes from human platelets,
bovine intestinal mucosa, yeast and E. coli were
all inhibited by this peptide [341-343].
The extent and the type of inhibition, however,
appears to be dependent on the enzyme source
[341-343]. This species-dependent difference in
inhibition patterns for glutathione reductase by
GSH reported here is, to the best of knowledge,
the first example of an observed functional
difference in the generally highly conserved
glutathione reductase enzyme. Physiologically, the
consideration of this inhibition has important
consequences because normal levels of GSH can
regulate the enzyme [343]. Presumably, the
enzyme will be inhibited by GSH under normal
cellular conditions and will therefore be less able
to convert oxidized form (GSSG) to reduced form
(GSH), providing a concentration of GSSG to be
maintained at higher than other wise expected
concentration [342].
1.4.4
UDP-Glucuronyl Transferase
Only a few years ago it was generally accepted,
that phase II metabolites of drugs, such as O- or Nglucuronides, are rapidly excreted following their
formation in the body and that these metabolites
Salah A. Sheweita
are not active or reactive [344,345]. The resulting
acyl glucuronides were found to be electrophiles,
reacting with sulfhydryl group. Conjugation with
D-glucuronic acid represents the major route for
elimination and detoxification of drugs and
endogenous compounds possessing a carboxylic
acid function [346,347]. Carcinogens and their
reactive metabolites may also be metabolized by
alternative routes (e.g., by conjugation or by
hydroxylase activities) to relatively harmless
intermediates that can be eliminated from the
body, although in some cases these may be further
transformed into highly reactive chemical species
[348,349]. As with the enzymes of carcinogen
activation those responsible for inactivation may
play pivotal roles in the determination of the target
tissue specificity of a particular carcinogen. It has
also been suggested that the sulfation of certain
chemical carcinogens could lead to more toxic
conjugates, which can cause cell necrosis [350352]. A major fraction of the N-hydroxy
derivatives of aromatic amines is converted to the
glucuronide, which is then excreted in the bile and
urine [350]. However, the glucuronide also may be
hydrolyzed to release the free N-hydroxy
arylamine, which is a potent electrophile [353].
1.4.5
Sulfate Conjugation
Many drugs are oxidized to a variety of
phenols, alcohols or hydroxylamines which can
then serve as excellent substrates for subsequent to
sulfates conjugation, forming the readily
excretable sulfate esters. However, inorganic
sulfate is relatively inert and must first be
activated by ATP [263]. For phenolic metabolites,
the key enzyme in this sequence is
sulfotransferase. The sulfotransferase enzymes are
soluble enzymes found in many tissues including
liver, kidney, gut and platelets and catalyze the
sulfation of drugs such as paracetamol,
isoprenaline and salicylamide and many steroids.
It appears that the sulphotransferase exist in
multiple enzyme forms with the steroid sulfating
enzymes being distinct from the sulfotransferases
responsible for drug conjugation reaction [354356]. It should be emphasized that sulfate
conjugation reactions are not as widespread or as
of quantitative importance as glucuronide
conjugation reactions, due in part to the limited
bioavailability of inorganic sulfate and hence
PAPS. This is particularly true when a drug is
actively metabolized to phenolic products or when
high body burdens of phenolic drugs are reached
(for example, in overdose), resulting in effective
saturation of this metabolic pathway [357].
Drug-Metabolizing Enzymes: Mechanisms and Functions
1.4.6
N-Acetyltransferase
Xenobiotic-metabolizing enzymes constitute an
important line of defense against a variety of
carcinogens. The wide variation in carcinogen
metabolism in human has long been regarded as an
important determinant of individual susceptibility
to chemical carcinogenesis. The carcinogenicity of
several arylamines and amides for the liver and the
urinary bladder has prompted studies on the
metabolism of these carcinogens and on their
reactive metabolites, which are catalyzed by
mixed-function oxidases in the hepatic
endoplasmic reticulum [358]. Distinct genes,
designated NAT1 and NAT2 code for N-acetyltransferase activities in human. NAT1 activity
appears to be monomorphically distributed in
human tissues, while the latter exhibits a
polymorphism that allows the detection of
phenotypically slow and rapid metabolizers [359].
The NAT2 polymorphism can have a significant
effect on individual susceptibility to aromatic
amine-induced
cancers.
N-Acetylation
of
arylamines represents a competing pathway for Noxidation, a necessary metabolic activation-step
occurring in the liver. The unconjugated Nhydroxy metabolites can then enter the circulation,
and be transported to the urinary bladder lumen,
where reabsorption and covalent binding to
urothelial DNA can occur [360]. Low activity of
arylamine N-acetyltransferase 2 (slow NAT2
acetylator) was consistently associated with
urinary bladder cancer risk [361]. Also, NAT2
plays a significant role in risk of lung cancer
among non-smokers Chinese women [362].
Some studies have shown that meat
consumption is associated with breast cancer risk.
Several heterocyclic amines, formed in cooking of
meats, are mammary carcinogens in laboratory
models [363,364]. Heterocyclic amines are
activated and rapid NAT2 activity may increase
risk associated with these compounds [363,364],
Since NAT2 increased the binding of quinoline, a
heterocyclic amine derivative, with DNA by 12
fold, while NAT1 increased such binding by 4 fold
[364].
1.4.7
Epoxide Hydrolase
Epoxide hydrolase is widely distributed
throughout the animal kingdom, including human.
In the rat, it almost occurs with highest activity
being found in the liver and smaller amount being
found in kidney, lung, and adrenal gland. In liver,
epoxide hydrolase occurs predominantly in the
Current Drug Metabolism, 2000, Vol. 1, No. 2 121
endoplasmic
reticulum
fraction,
membranes, and the cytosol [365].
nuclear
The soluble epoxide hydrolase (sEH) plays a
significant role in the biosynthesis of
inflammatory mediators as well as xenobiotic
transformations [366]. Epoxide hydrolase is
induced by most of the xenobiotic inducers of the
mixed-function oxidase system. Decamethylcyclopentasiloxane (D5) is a cyclic siloxane with a
wide range of commercial applications. Liver
microsomal epoxide hydrolase activity and
immunoreactive protein increased 1.7- and 1.4fold, respectively, in the D5-exposed group [367].
The naturally occurring organosulfur compounds
(OSCs) diallyl sulfide (DAS), diallyl disulfide
(DADS) and dipropyl sulfide (DPS) were studied
with respect to their effects on microsomal
epoxide hydrolase (mEH). DADS increased the
mEH levels in the liver, intestine, and kidney,
while DAS and DPS moderately induced mEH
level in the liver [368]. A series of organosulfur
compounds were developed as chemopreventive
active compounds against hepatotoxicity and
carcinogenicity of aflatoxin B1 [369]. The
mechanism of chemoprotection involved in the
inhibition of the P450-mediated metabolic
activation of chemical carcinogens and
enhancement of electrophilic detoxification
through induction of epoxide hydrolase, which
would facilitate the clearance of activated
metabolites through conjugation reaction [369]. .
Although hydrolysis in most of the cases result in
detoxication, in some cases hydrolysis may lead to
activated
molecules
that
may
attack
macromolecules (proteins, RNAs, DNAs),
resulting in toxicity [370].
On the other hand, the discovery of substituted
ureas and carbamates as potent inhibitors were
found to enhance cytotoxicity of trans-stilbene
oxide, which is active as the epoxide, but reduce
cytotoxicity of leukotoxin, which is activated by
epoxide hydrolase to its toxic diol [366]. They also
reduce toxicity of leukotoxin in vivo in mice and
prevent symptoms suggestive of acute respiratory
distress syndrome [366].
Genetic polymorphisms of biotransformation
enzymes are in a number of cases a major factor
involved in the interindividual variability in
xenobiotic metabolism and toxicity [371]. This
may lead to interindividual variability in efficacy
of drugs and disease susceptibility. Polymorphisms in exons 3 and 4 of microsomal epoxide
hydrolase in 101 patients with colon cancer and
compared the results with 203 control samples.
122
Current Drug Metabolism, 2000, Vol. 1, No. 2
The frequency of the exon 3 T to C mutation was
higher in cancer patients than in control [372].
This sequence alteration changes tyrosine residue
113 to histidine and is associated with lower
enzyme activity when expressed in vitro.
Therefore, slow epoxide hydrolase activity may be
a risk factor for colon cancer [372].
Salah A. Sheweita
PAPS
=
3'-Phosphoadenosine-5'phosphosulfate
MAB
=
N-Methyl-4-aminoazobenzene
DAB
=
N, N-Dimethylaminoazobenzene
GSH
=
Glutathione (reduced form)
CONCLUSION
GSSG
=
Glutathione (oxidized form)
This review represents the importance of
cytochrome P450 in the oxidation of xenobiotics
and carcinogens. Cytochromes P450 are multigene
families with broad substrate specificities. The
expression of different P450 isozymes is
dependent on many endogenous or exogenous
factors. Each P450 isozyme is responsible for
oxidation of certain drug into more or less active
metabolites. The toxicity and carcinogenicity of
chemical carcinogens are mainly dependent on the
level of their activating enzymes and also on the
balance with detoxifying enzymes such as
glutathione S-transferase.
GST
=
Glutathione-S-transferase
GR
=
Glutathione reductase
NAT
=
N-Acetyltransferase
EH
=
Epoxide hydrolase
DAS
=
Diallyl sulfide
DADS
=
Diallyl disulfide
DPS
=
Dipropyl sulfide
ABBREVIATIONS
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