DRUG METABOLIZING ENZYMES IN HUMANS AND ANIMAL MODELS

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ACCOMPLISHMENTS: Our laboratory has discovered polymorphisms in CYP2C19, CYP2C9, and more recently CYP2C8 which affect the way humans can metabolizes specific drugs. CYP2Cl9 metabolizes the drugs omeprazole, mophenytoin, valium, certain barbiturates, certain antimalarials, and the pesticide phorate. We have identified 11 alleles . We have identified a new defective CYP2C9 allele was found in an individual who was a PM for the metabolism of phenytoinand was shoing excessive toxicity to the drug. CYP2C9 is very important in metabolism of a wide variety of clincal drugs such as heparin, tolbutamide, phenytoin, ibuprofen, and antiinflammatories. We isolated the gene for CYP2C8 from humans. 20SNPs were found in 72 individuals from 3 racial groups resequenced for this gene. Two polymorphic alleles with amino acid variations were discovered. 1)Ile269Phe (CYP2C8*2) and 2) Arg139Lys and Lys399Arg (CYP2C8*3). Genetic tests were devised. CYP2C8*2 is found in African-Americans, and CYP2C8*3 primarily in Caucasians. Using recombinant systems, CYP2C8*3 is defective for metabolizing the anticancer drug taxol in a recombinant system as well as in metabolizing the endogenous compound . CYP2C8 appears to be well expressed in human heart and is therefore of additional clinical interest. CYP2C8*2 appears to have a modest effect on taxol metabolism in vitro. We have also found that CYP3C8*3 is defective in metabolizing arachidonic acid, an important physiological mediator. We have localize CYP28 to human heart, both muscle and endothelial cells. Therefor CYP2C8 polymorphisms could potentially have importance in heart disease, coronary artery disease, etc. We are examining clinical populations exposed to taxol as well as those with chronic heart disease for the incidence of these polymorphisms.