Drug Metabolizing Enzymes In Humans And Animal Models

点击翻译按钮获取中文摘要

ACCOMPLISHMENTS: We have identified genetic polymorphisms in the CYP family in humans which are responsible for the variable metabolism of certain drugs and environmental chemicals and altered susceptibility of humans to these chemicals. By resequencing efforts we have found 21SNPs in 72 individuals from 3 racial groups resequenced for human CYP2C8 including two alleles with coding changes : CYP2C8*2( Ile269Phe) and CYP2C8*3(Arg139Lys and Lys399Arg). Genetic tests showed CYP2C8*2 is found in African-Americans, and CYP2C8*3 primarily in Caucasians. Using recombinant cDNA expression systems, we found CYP2C8*3 is defective in the metabolism of the anticancer drug taxol as well as the endogenous compound arachidonic acid. CYP2C8 is expressed in human heart and blood vessels and is therefore of additional clinical interest. CYP2C9. A new null mutation was found in CY2C9 which decreased metabolism of the phenytoin by 85% in an African-American patient exhibiting severe clinical toxicity to the anticonvulsant phenytoin. The individual was homozygous for a new deletion mutant of CYP2C9. This is the first example of a null polymorphism in this clinically important enzyme. Population studies showed that the mutation was found in African-Americans but absent or rare in Caucasians. New polymorphisms have been discovered in CYP3A4 which metabolizes almost half of all clinically known drugs. Two amino acid changes affect catalytic activity toward the organophosphorus pesticide chlorpyrifos, and the hormone testosterone. The effects of these amino acid changes are being addressed in a bacterial cDNA expression system. Resequencing of CYP2C9 in 72 individuals has uncovered six new coding changes. The consequences of these are being studied using site-directed mutagenesis and cDNA expression systems. CYP2C19 metabolizes the antiulcer drug omeprazole, the anticonvulsant mephenytoin, valium, certain barbiturates, activates certain antimalarials, and sulfoxidizes the pesticide phorate. Nine new polymorphisms have been detected in CYP2C19. Their effects will be addressed in recombinant cDNA expression systems.