Cytochromes P450 (CYP) are a major source of variability in drug pharmacokinetics
and response. Of 57 putatively functional human CYPs only about a dozen enzymes, belonging
to the CYP1, 2, and 3 families, are responsible for the biotransformation of most
foreign substances including 70-80% of all drugs in clinical use. The highest expressed
forms in liver are CYPs 3A4, 2C9, 2C8, 2E1, and 1A2, while 2A6, 2D6, 2B6, 2C19 and
3A5 are less abundant and CYPs 2J2, 1A1, and 1B1 are mainly expressed extrahepatically.
Expression of each CYP is influenced by a unique combination of mechanisms and factors
including genetic polymorphisms, induction by xenobiotics, regulation by cytokines,
hormones and during disease states, as well as sex, age, and others. Multiallelic
genetic polymorphisms, which strongly depend on ethnicity, play a major role for the
function of CYPs 2D6, 2C19, 2C9, 2B6, 3A5 and 2A6, and lead to distinct pharmacogenetic
phenotypes termed as poor, intermediate, extensive, and ultrarapid metabolizers. For
these CYPs, the evidence for clinical significance regarding adverse drug reactions
(ADRs), drug efficacy and dose requirement is rapidly growing. Polymorphisms in CYPs
1A1, 1A2, 2C8, 2E1, 2J2, and 3A4 are generally less predictive, but new data on CYP3A4
show that predictive variants exist and that additional variants in regulatory genes
or in NADPH:cytochrome P450 oxidoreductase (POR) can have an influence. Here we review
the recent progress on drug metabolism activity profiles, interindividual variability
and regulation of expression, and the functional and clinical impact of genetic variation
in drug metabolizing P450s.
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