DRUG METABOLIZING ENZYMES IN HUMANS AND ANIMAL MODELS

某些CYP酶在人体内是多态的。一种多态性影响

Certain CYP enzymes are polymorphic in man. One polymorphism affects the metabolism of mephenytoin and the commonly used antiulcer drug omeprazole as well as antimalarials and certain other drugs. This polymorphism varies in different racial populations. We have cloned and identified the two principle defects. We have developed diagnostic PCR tests for the two defects. The specificity of the tests are 100% and the sensitivity is ~93% in Caucasians and 100% in Orientals. These account for 100% of Oriental poor metabolizers and >90% of Caucasian and >90% of black poor metabolizers. We have examined the frequency of these defects in large numbers of Caucasians, Japanese, Chinese, Filipinos, and American black populations. The first defect m1 accounts for 75-90% of poor metabolizers, while the 2nd defect m2 accounts for the remainder of Oriental PMs but is rare in Caucasians. The allele frequencies varies in different racial groups. This polymorphism accounts for decreased ability to metabolize the drug omeprazole in vivo. We have also identified two normal wild-type alleles. We have expressed the cDNAs for all known members of the 2C subfamily in yeast and shown that CYP2C19 and CYP3A are the principal omeprazole 5'-hydroxylases while other CYP2C enzymes have little activity. We are testing which amino acids are important in this function by site-directed mutagenesis. DNA from two individuals who metabolize tolbutamide poorly has been sequenced and two potential defects have been identified. The allele frequency of these alleles have been determined in Caucasians, blacks, and Orientals. These alleles is being tested toward the drug tolbutamide and the anticancer agent cyclophosphamide.