Download Xenobiotics must be metabolized before being excreted

Metabolism of Xenobiotics
Biomedical Importance
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Human exposure to foreign chemicals (=xenobiotics) creates the need tob e able to excrete
those substances especially if they are harmful to the body
Foundation for understanding pharmacology and therapeutics, pharmacy, toxicology
management of cancer and drug addiction.
Xenobiotics must be metabolized before being excreted
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Most of the more than 200000 manufactured environmental chemicals are subject to
metabolism (=chemical alteration)
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Liver is the main organ for chemical metabolization even though occasionally a xenobiotic might
be excreted unchanged
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There are at least 30 different enzymes involved in xenobiotic metabolism which happens in 2
phases:
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Phase1:
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Major reaction is hydroxylation
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Hydroxylation may terminate the action of a drug, but this is not always the
case
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In addition to hydroxylation these enzymes also catalyze other reactions such as:
Hydroxylation is catalyzed by members of the monooxygenase or cytochrome
P450 enzyme class
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Deamination
Dehalogenation
Desulfuration
Epoxidation
Peroxygenation
Reduction
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Reactions involving hydrolysis (eg, catalyzed by esterases) and certain other
non-P450-catalyzed reactions also occur in phase 1
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In certain cases , phase 1 metabolic reactions convert xenobiotics from inactive
forms to biologically active compounds, in these cases the original xenobiotics
are referred to as “prodrugs” or “procarcinogens”
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In some cases phase 1 reactions convert the active compounds into less active
or inactive forms prior to conjucation.
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In yet other cases, the conjugation reactions convert the active products of
phase 1 reactions into less active or inactive species, which are subsequently
excreted with urine or bile.
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In a few cases the conjugation may increase the biologic activity of the
xenobiotics.
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Phase2:
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Hydroxylated or other compounds produced in phase 1 are converted by specific
enzymes to various polar metabolites by conjugation with:
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Glucuronic acid
Sulfat
Acetate
Glutathione
Certain amino acids
Or by methylation
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This al happens to increase the water solubility (=polarity) and thus excretion
from the body
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Because of the examples mentioned in phase 1 the term “detoxification” is not
always appropriate.
Isoforms of cytochrome P450 hydroxylate a countless number of xenobiotics
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Hydroxylation is the major reaction in phase 1 and the responsible enzymes are called
monooxygenases or cytochrome P450s, of the later it is assumed that there are about 60
cytochrome P450 genes present in humans
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The reaction catalyzed by a monooxygenase (cytochrome P450) is as follows:
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In addition to xenobiotics represented by RH above, endogenous compounds such as certain
steroids, eicosanoids, fatty acids, and retinods are also generally hydrophilic substrates which
are rendered more hydrophilic by hydroxylation
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Cytochrome P450 is considered to be the most versatile biocatalyst and its function is shortly
described here:
Isoforms of the Cytochrome P450 make up a superfamily of heme –
containing enzymes
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Nomenclature of the Cytochrome P450 isoforms:
o The abbreviated root CYP denotes a cytochrome P450.
 CYP
o It is followed by an Arabic number denoting the family, cytochrome P450 isoforms are
considered the same family if they exhibit 40% or more amino acid sequence identity.
 CYP3
o The Arabic number is followed by a capital letter indicating the subfamily, if two or more
members exist. Cytochrome P450 isoforms are considered to be in the same subfamily if
they exhibit more than 55% sequence identity.
 CYP3A
o The individual Cytochrome P450 is then denoted with a number following the letter.
 CYP3A1 is the 1st Cytochrome P450 of the A subfamily of the 3rd family
o The nomenclature for the genes encoding the cytochrome p450 is identical to that
describes above except that italics are used so the gene encoding CYP3A1 is CYP3A1
o CYP3A is the most important cytochrome P450 involved in drug metabolism, because of
its abundance in liver and intestine, it can act on a wide variety of drugs from almost
every class but its activity is a bit unpredictable since it can vary by almost 400fold due
to inhibition and induction and therefore causing dosage problems
Cytochrome P450s are hemoproteins
They are widely distributed across species, including bacteria
They are present in the highest amount in liver cells and enterocytes but a probably oresent in
all tissues.
o In liver and most other tissues they are mainly present in the membranes of the smooth
endoplasmic reticulum, which constitute part of the microsomal fraction when tissue is
subjected to subcellular fractionation. In hepatic microsomes, cytochrome p450 can
comprise as much as 20% of the total protein
o In the adrenal they are found in mictochondria as well as in the endoplasmic reticulum.
The mitochondrial cytochrome P450 differs from the microsomal cytochrome P450 in
the way that it uses an NADPH-linked flavoprotein, adrenodoxin Reductase and a
nonheme iron-sulfur protein, adrenodoxin.
There are at least 6 isoforms of cytochrome P450 present in the liver
o Each of them have wide and overlapping substrate specificities and acting on both
xenobiotics and endogenous compounds.
NADPH, not NADP and especially not NSDAP is involved in the reaction mechanism of
cytochrome P450.
o The enzyme that uses NADPH to yield the reduced cytochrome P450, shown at the left
hand side of the equation below is called NADPH-cytochrome P450 reductase. Electrons
are transferred from NADPH to NADPH-cytochrome P450 reductase and then to
cytochrome p450.
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This leads to the reductive activation of melcular oxygen and one atom of oxygen is
subsequently inserted into the substrate. Cytochrome b5, another hemoprotein found in
the membranes of the smooth endoplasmic reticulum, may be involved as an electron
donor in some cases.
HARPERS SECTION VI SPECIAL TOPICS METABOLSIM OF XENOBIOTICS (REAL BOOK PAGE
634 EBOOK 627) continne with (7) lipids!!!!
Biomedical Importance
-
Human exposure to foreign chemicals (=xenobiotics) creates the need tob e able to excrete
those substances especially if they are harmful to the body
Foundation for understanding pharmacology and therapeutics, pharmacy, toxicology
management of cancer and drug addiction.