INHIBITION OF UDP-GLUCURONOSYLTRANSFERASE ACTIVITY IN RAT-LIVER MICROSOMES BY PYRIMIDINE-DERIVATIVES

Thirty-one differently substituted pyrimidine bases were tested for th eir inhibitory effect on the glucuronidation of 4-nitrophenol and phen olphthalein by rat liver microsomes, 5-Nitrouracil (compound 1) and it s isomer 4,6-dihydroxy-5-nitropyrimidine (compound 2) were the most po tent and selective inhibitors of 4-nitrophenol glucuronidation, withou t any effect on the phenolphthalein conjugating activity of UDP-glucur onyitransferase (UGT). Kinetic studies with compound 1 revealed a mixe d type of inhibition toward the acceptor substrate 4-nitrophenol and a n atypical competitive type of inhibition toward UDP-glucuronic acid, with apparent Ki values of 0.11 and 0.2 mM, respectively, Two benzylam ino-substituted pyrimidines (compounds 10 and 12) and an erotic acid d erivative (compound 25) inhibited both 4-nitrophenol and phenolphthale in UGT activities.