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BIOTRANSFORMATION,
Drug metabolism,
detoxification
netversion
Fate of Xenobiotics
• Enzymatic conversion
• Elimination without any chemical
reaction
• Spontaneous chemical conversion
• Accumulation without conversion
Cellular metabolism of xenobiotocs
1st phase
2nd phase
3rd phase
phase I metabolism – purpose:
„function groups” are formed
•
•
•
•
Oxidation
Reduction
Hydrolysis
Hydratation
Formation of a more polar metabolite than
the original substrate, better chance for
excretion, lipid soluble → water soluble
Cytochrome P450 system
flavoprotein
lipid – (membrane – SER)
hemoprotein
Flavoprotein:
NADPH – P450 oxidoreductase
Lipid:
phosphatidyl choline
Hemoprotein:
Cytochrome b5
Cytochrome P450
Reductase – P450 ratio: 1 : 10
1 : 100
Role of the liver in drug metabolism
-first pass effect – one way street – chemical factory
Portal circulation
Cytochrome P450 gene
superfamily
• In mammals 8 families, in drug metabolism 4:
CYP1, CYP2, CYP3, CYP4
• Expressed mainly in liver, but also in lungs,
intestines, skin and kidneys
• Gene evolution, protein filogenesis – natural
selection – survival value
• Ancestor gene 3,5 bilion yrs (22 exon),
1,5 bilion yrs ago: plant ↔ animal separation,
400 million yrs ago: surface ↔ ocean
1.5 billion yrs
400 million yrs
today
Figure 3. Contribution of major human P450s to the Phase I metabolism of all drugs currently
marketed (25). The compilation is intended to be approximate and will vary with changes in
drugs. For tables of raw data see Rendic (22). The non-P450 enzymes include alcohol and
aldehyde dehydrogenases, flavin-containing monooxygenases, etc.
CYP 1
2 genes
even 100 fold inducibility
Inducers:
metilcholantrene
dioxin derivatives
industrial technologies
environmental pollution
cigarette smoke
Inducibility
incidence of bronchial arcinoma
Substrates:
Policyclic aromatic carbohydrates (PAH): benzpyrene, benzanthracene etc.
Medicines: teophyllin, phenacetin etc.
CYP 2
(A – H)
Inducers:
phenobarbital
Ethanol
Aceton
Diazepam derivatives
CYP 2A steroids, testosteron
CYP 2B progesteron, D3 vitamin, antiepileptics
CYP 2C mephenytoin - antiepileptics
CYP 2D antidepressants, beta blockers, antihypertensive agents,
debrisoquine metabolism
PM poor metabolizer
EM extensive metabolizer
Inducibility
gastrointestinal tract carcinomas,
bronchial carcinoma incidence
CYP 2E etanol, aceton
diabetes mellitus, starvation
Figure 1. Relative rates of CYP2D6 activity in a Caucasian population (4). CYP2D6 activity is
represented as the ratio of unmetabolized drug (here, debrisoquine) to drug metabolite (4hydroxydebrisoquine) collected from the urine following a single dose. The distribution is the result
of the existence of more than seventy alleles in the population (see http://www.imm.ki.se/CYPalleles/).
Early research labeled individuals as "extensive metabolizers" (green) and "poor metabolizers"
(blue) (5). The "ultrarapid metabolizer" phenotype (red) can result from inherited gene
amplification
Figure 4. Significance of unexpectedly low metabolism of a drug by P450s. The typical pattern seen
with the majority of the population (extensive metabolizers) is shown in the upper panel, where the
plasma level of the drug is maintained in a certain range over the period of several consecutive
doses (arrows indicate multiple doses). Unusually slow metabolism (lower panel) occurs when a
poor metabolizer (without previous knowledge of phenotype) receives the same dose, resulting in an
elevated plasma level of the drug. Adapted from
CYP 3
Inducers:
steroids
Oral contraceptives
PCN – pregnenolon carbonitril
Substrates:
Antibiotics
nifedipin
cyclosporin
CYP 4
Inducer:
clofibrate – antihyperlipemic agent
Substrates:
Fatty acids
eicosanoids