Inhibition of UDP-glucuronosyltransferases in rat liver microsomes by natural mutagens and carcinogens.
Eight toxic compounds of natural origin present in the human diet or used as drugs were tested as inhibitors of UDP-glucuronosyltransferase (UGT) activity in rat liver microsomes with 1-naphthol (1-NA), phenolphthalein (PPh) and 4-nitrophenol (4-NP) as substrates. Strong inhibitory effects were observed with tannic acid (tannin) and the antifungal drug griseofulvin (GF): at a concentration of 1 mM, the two compounds completely suppressed the glucuronidation of 1-NA and PPh, respectively. A concentration of 0.1 mM still proved to be highly inhibitory, and even at a concentration as low as 50 microM, tannin produced nearly 50% inhibition of 1-NA conjugation. The UGT isoforms converting 4-NP were less sensitive to the tested compounds (with the exception of GF). Kinetic studies with tannin revealed an uncompetitive type of inhibition toward 1-NA, with an apparent Ki value of 20 microM. The inhibition by GF was non-competitive with respect to PPh and was of a mixed type toward UDP-glucuronic acid, with apparent Ki values of 40 microM and 30 microM, respectively. Tannin and GF did not act as substrates for rat microsomal UGT.
Grancharov
K
K
Institute of Molecular Biology, Bulgarian Academy of Sciences, Sofia.
Engelberg
H
H
Naydenova
Z
Z
Müller
G
G
Rettenmeier
A W
AW
Golovinsky
E
E
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000633:toxicity*; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors*; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology*; D009153:Mutagens / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar
D002273:Carcinogens; D004791:Enzyme Inhibitors; D009153:Mutagens; D014453:Glucuronosyltransferase