Review articleCYP2C19 genotype determines enzyme activity and inducibility of S-mephenytoin hydroxylase☆
Introduction
Pharmacogenetic studies have established the importance of polymorphic drug-metabolizing enzymes in the differential response of patients to drugs. Among the drug-metabolizing enzymes, cytochrome P4502C19 (CYP2C19) has become a subject of extensive studies concerning individual variation of drug metabolism. The association between decreased drug clearance and activity of CYP2C19, the inherited nature of the deficiency, and its frequency and clinical importance were evaluated extensively. During the past over 10 years, the CYP2C19 polymorphism has been studied at the protein and gene level. Analysis of allele frequencies in different populations revealed individual and interethnic differences that contribute to the molecular mechanisms responsible for interindividual variations in drug metabolisms and responses.
In recent years, we demonstrated that CYP2C19 genotype is a major factor determining the metabolism of drugs mediated via CYP2C19. We also confirmed that the drug-induced induction of CYP2C19 is related to the genotype of the enzymes. As a result of the genotype effect, interindividual variations in drug metabolism may result from interindividual differences in composition of a particular polymorphic allele and mutations that code for enzymes with abnormal activity which occur with altered frequency in the individuals.
In this review, we summarize studies in our laboratory on the individual variations in drug metabolism mediated by polymorphic CYP2C19, and the role of genotype in the metabolism of certain currently used drugs and the inducibility of this enzyme.
Section snippets
Genetic polymorphism of CYP2C19
The genetic polymorphism of CYP2C19 was revealed by the discovery of deficient 4′-hydroxylation of mephenytoin (3-methyl-5-phenyl-5 ethylhydantoin; Mesantoin), a now rarely used anticonvulsant drug. Human can be characterized as poor (PM) or extensive metabolizers (EM) with use of racemic mephenytoin as a phenotyping drug [1], [2], and CYP2C19 has been identified as the major S-mephenytoin (S-MP) hydroxylase in human [3], [4]. This polymorphism affects the metabolism of many other clinically
4′-Hydroxylation of S-MP
It has been found that there is a large interethnic difference in the amount of CYP2C19 protein in liver microsome. The amount of CYP2C19 in microsome from Japanese and Caucasians is 0.8% and 1.4% of total CYP450, respectively. The protein contents of this enzyme are determined by CYP2C19 genotype as shown in an in vitro study in that the amount of CYP2C19 in microsome is highest in the individuals homozygous of wild-type gene (CYP2C19*1/*1, 9.2±3.5 pmol/mg protein) and lowest in homozygous of
Genotype of CYP2C19 determines the enzyme inducibility
It is well known that some of the enzymes in P4502C subfamily (including CYP2C19) can be induced in both animals and humans. Also, chronic use of MP causes autoinduction [21]. Treating EMs and PMs of S-MP with rifampicin, using MP as a probe, the CYP2C19 activity was inducible in EMs but not in PMs [22]. Recently, we found that some of the PMs of S-MP whose genotypes were defined as CYP2C19*2/*2 or CYP2C19*2/*3 excreted as much as 8% of the dose as 4′-hydroxymephenytoin (4′-OH-MP). In addition,
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Project supported by the National Natural Science Foundation of China, NoF39330230 and by China Medical Board of New York Grants 92-568 and 99-697.