There are relatively few drugs that undergo S-methylation but the enzymes are important for the detoxication of xenobiotic thiol compounds which tend to be toxic, and clinically significant because of polymorphisms that occur in thiopurine methyltransferase (TPMT). The gene for human TPMT, located on chromosome 6p22, codes for a 28kDa cytosolic enzyme that catalyzes the methylation of aromatic and heteroaromatic thiols.117 Substrate groups include thiophenols and the oncolytic and immunosuppressive agents 6-mercaptopurine (6-MP) and azathioprine. Polymorphic disposition of these two latter drugs is important in cancer therapy, because a poor metabolizer phenotype is a major risk factor for severe hemotoxicity resulting from an exaggerated pharmacological effect of thioguanine nucleotides in nontarget hemopoietic cells. The distribution of TPMT activity is trimodal: approximately 1 in 300 individuals are poor metabolizers requiring substantial dose reduction of 6-MP and azathioprine. The TPMT polymorphism is as a paradigm for personalized medicine in the field of pharmacogenomics.120
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