Biotransformations of Drugs and Chemicals
fact that the concentrations of some of
the enzymes, most notably the cytochrome
P450 monooxygenases (see Sect. 3.1), are
transiently increased by exposure to spe-
ciFc substrates or inhibitors. This selective
induction of enzyme forms that are re-
quired to deal with speciFc xenobiotics
enhances the flexibility of the system in its
response to xenobiotic exposure.
Phase I Enzymes
Cytochrome P450 and Flavin
hemoproteins that are found in highest
concentrations in the liver, kidney, nasal
tissues, and lungs but are present in
smaller amounts in most other organs.
The name cytochrome P450 derives from
the distinctive absorption maximum at ap-
proximately 450 nm of the ferrous–carbon
monoxide complex of these enzymes. The
genes for more than 1000 cytochrome
P450 enzymes have been identiFed in
prokaryotic and eukaryotic species. Ap-
proximately 60 such enzymes are found in
the human genome. A nomenclature sys-
tem has been developed that is based on
division of the superfamily of cytochrome
P450 enzymes according to their degree
of sequence identity. With few exceptions,
the members of a cytochrome P450 fam-
ily share
40% amino acid identity and
the members of a subfamily
55% iden-
tity. In this nomenclature, cytochrome
P450 enzymes are designated as, for ex-
ample, CYP4A1, in which the number
after the preFx CYP identiFes the family,
the subsequent letter the subfamily, and
the Fnal number the individual enzyme
within the subfamily. A similar nomencla-
ture has been developed for other families
of drug-metabolizing enzymes, including
the glucuronyl transferases and sulfotrans-
ferases. Citations prior to 1987 employ
nonsystematic nomenclatures.
The tissue levels of the different cy-
tochrome P450 enzymes in an individual
are controlled by genetic and environ-
mental factors. Genetic variability in the
expression of the various cytochrome P450
enzymes is well established and gives rise
to populations with distinct metabolic pat-
terns. Important differences exist in the
ability of individuals to metabolize drugs
owing to the existence of populations with
high and low activities of, for example, the
CYP2D6 form of cytochrome P450 respon-
and a variety of other drugs. In addition
to genetic factors, the levels of cytochrome
P450 enzymes are modulated by diet, age,
disease, gender, and hormonal status. The
ability of drugs and xenobiotics to alter the
proFle of cytochrome P450 enzymes in an
individual by elevating the concentrations
of speciFc forms is particularly relevant
in this context. The increase in the lev-
els of certain enzymes by a xenobiotic,
enzyme induction
, can be mediated
by several mechanisms, among which the
most important are an increase in tran-
scription of the message for the enzyme,
stabilization of the RNA transcript, and
stabilization of the enzyme itself.
The mechanism of induction of the cy-
tochrome P450 enzyme CYP1A1 involves
binding of the inducer to a soluble recep-
tor, termed the
aryl hydrocarbon receptor
AHR), that translocates to the nucleus and
enhances the expression of the appropri-
ate gene. Comparable receptor-mediated
mechanisms have more recently been
identiFed for the induction of other classes
of cytochrome P450 enzymes. The classical
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