Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG). A genetic polymorphism regulating TPMT activity in human tissue is an important factor responsible for individual differences in the toxicity and therapeutic efficacy of these drugs. Because of the clinical importance of this polymorphism, we studied 18 purine derivatives, including ribonucleosides and ribonucleotides, as potential substrates for purified human kidney TPMT. Sixteen of the compounds studied were substrates for the enzyme, with Kmvalues that varied from 29.1 to 1270 μM and with Vmaxvalues that varied from 75 to 2340 U/mg protein. The thiopurines tested had Kmvalues that were uniformly lower than were those of the corresponding ribonucleosides or ribonucleotides. 6-Selenopurine derivatives had the lowest Kmvalues of the compounds studied. Finally, oxidized purines with an OH in the 8-position were methylated by the enzyme, but 2-OH compounds were potent inhibitors of TPMT. © 1994.
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