The CYP enzymes metabolize drugs and xenobiotics, and polymorphisms in some of these enzymes account for variability in metabolism in man. We have identified three new defects in CYP2C19 responsible for poor metabolizers (PMS) of the anticonvulsant drug mephenytoin and the antiulcer drug omeprazole and developed genetic tests for two of these polymorphisms. Genetic tests developed in our laboratory identify approximately 100% of Oriental and approximately 84% of Caucasian PMS in clinical studies. cDNA expression studies confirm that 2C19 is the principle omeprazole 5-hydroxylase. A polymorphism in CYP2C9 responsible for PMS of the antidiabetic drug tolbutamide has been identified as the CYP2C9-Leu allele which has decreased affinity in cDNA expression studies for certain substrates such as the anticoagulant warfarin and the antidiabetic drug tolbutamide. cDNA expression and site-directed mutagenesis studies are being used to identify amino acids which are important in the substrate specificity of the CYP2C subfamily. Amino acid 99 and amino acid 220 have been identified as being important for selectivity of CYP2C19 for omeprazole but are not sufficient to confer selectivity for mephenytoin. Additional studies are directed toward identifying additional defects in CYP2C19 and developing and improving the accuracy of genetic testing. Site-directed mutagenesis studies are identifying which additional amino acids confer specificity for additional drugs and endogenous chemicals such as omeprazole, mephenytoin, warfarin and arachidonic acid. Partial gene structures for possibly new CYP 2C enzymes have been identified and gene cloning studies are attempting to identify the total gene structure for these genes, and identify their mRNA products in liver and extrahepatic tissues. cDNA expression studies are directed toward identifying which CYP2C enzymes are involved in pesticide metabolism, and metabolism of the antimalarial proguanil.
Showing the most recent 10 out of 37 publications
