DRUG METABOLIZING ENZYMES IN HUMANS AND ANIMAL MODELS

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Aims: To identify genetic polymorphisms in the CYP2C subfamily in humans and laboratory animals which are responsilble for the variable metabolism by certain individuals to particular drugs. For these pathways, population studies show that humans can be divided into two groups , poor metabolizers (PMS) and extensive metabolizers (PMS). PMS have altered susceptibility to clinically administered drugs. These polymorphisms can potentially also affect metabolism of environmental compounds and affect susceptibility to environmental diseases. Human CYP2C19 is polymorphic. This enzyme metabolizes a variety of drugs including the antiulcer drug omeprazole and the anticonvulsant mephenytoin. We have identified nine mutant alleles (including five new alleles this year) contributing to the poor metabolizer phenotype and two wild-type alleles . Poor metabolizers make up 3-5% of Caucasian populations but 13-22% of Oriental populations. Two new poor metabolizer alleles were identified which were single amino acid mutations in exon 3. One was completely inactive and the other had approximately 10% of the wild type activitiy for tolbutamide and mephenytoin. Family studies showed another mutation in exon two segregated with CYP2C9*2 (a splice variant) and consisted of a new variant allele of this inactive protein. A fourth allele was in the heme binding region and was completely inactive. The last new mutation was a splice variant. These bring the accuracy of the genetic tests to ~96-98%. One poor metabolizer of a new drug glizipide and the antidiabetic drug tolbutamide was identified as a variant CYP2C9*3. The CYP28 gene structure has been established. A new CYP2C was identified in the dog which is polymorphic and present in only 10% of dogs. This may influence the toxicity and metabolism of certain compounds in the dog which is a test model for drug toxicology studies.