Enzyme genetic polymorphism

Clinical response to mercaptopurine is related to whole-blood concentrations of the metabolite 6-thioguanine, and hepatotoxic-ity is correlated with another metabolite, 6-methylmercaptopurme. Metabolic inactivation of azathioprine and mercaptopurine occurs by thiopurine S-methyltransferase, which exhibits genetic polymorphism. Enzyme-deficient patients are at greater risk of bone marrow suppression from these agents. Determination of enzyme activity may be necessary to determine which patients require lower doses of these agents. 

In vivo azathioprine is rapidly converted into its active metabolite 6-mercaptopurine by the enzyme thiopurine methyltransferase (TPMT). The active agent inhibits IMPDH function. Furthermore, it also acts as antimetabolite of the RNA and DNA synthesis particularly in T-lymphocytes leading to cell death. Due to genetic polymorphism of TPMT, therapy may fail, thus it is currently discussed whether individual patients should be monitored before the use of azathioprine. 

Sun F, Tsuritani 1, Yamada Y Contribution of genetic polymorphisms in ethanol-metabolizing enzymes to problem drinking behavior in middle-aged Japanese men. Behav Genet 32 229—236, 2002... 

Masimirembwa, C. M. Hasler, J. A. (1997). Genetic polymorphism of drug metabolising enzymes in African populations implications for the use of neuroleptics and antidepressants. Brain. Res. Bull., 44(5), 561-71. 

It has now been established that genetic polymorphisms in drug metabolizing enzymes such as the cytochrome P450s (CYP) and the phase II enzyme, thiopu-rine methyltransferase, are responsible for inter-individual variability in response and adverse reactions [12, 13]. However, at the present time, the impact of poly-... 

Tanaka E. Update genetic polymorphism of drug metabolizing enzymes in humans. J Clin Pharm Ther 1999 24 323-329. 

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