Inhibition of UDP-glucuronyltransferase activity in rat liver microsomes by pyrimidine derivatives.
Thirty-one differently substituted pyrimidine bases were tested for their inhibitory effect on the glucuronidation of 4-nitrophenol and phenolphthalein by rat liver microsomes. 5-Nitrouracil (compound 1) and its isomer 4,6-dihydroxy-5-nitropyrimidine (compound 2) were the most potent and selective inhibitors of 4-nitrophenol glucuronidation, without any effect on the phenolphthalein conjugating activity of UDP-glucuronyltransferase (UGT). Kinetic studies with compound 1 revealed a mixed type of inhibition toward the acceptor substrate 4-nitrophenol and an atypical competitive type of inhibition toward UDP-glucuronic acid, with apparent Ki values of 0.11 and 0.2 mM, respectively. Two benzylamino-substituted pyrimidines (compounds 10 and 12) and an orotic acid derivative (compound 25) inhibited both 4-nitrophenol and phenolphthalein UGT activities.
Naydenova
Z
Z
Institute of Molecular Biology, Bulgarian Academy of Sciences, Sofia.
Grancharov
K
K
Shopova
M
M
Golovinsky
E
E
D000818:Animals; D004791:Enzyme Inhibitors; D005965:Glucuronates / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D009596:Nitrophenols / Q000378:metabolism; D020113:Phenolphthalein; D010635:Phenolphthaleins / Q000378:metabolism; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014498:Uracil / Q000031:analogs & derivatives / Q000494:pharmacology
D004791:Enzyme Inhibitors; D005965:Glucuronates; D009596:Nitrophenols; D010635:Phenolphthaleins; D011743:Pyrimidines; D014498:Uracil; C057449:5-nitrouracil; D020113:Phenolphthalein; D014453:Glucuronosyltransferase; C024836:4-nitrophenol