title: Inhibition of UDP-glucuronosyltransferases in rat liver microsomes by natural mutagens and carcinogens.
abstract: 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.
authors.affiliation: Institute of Molecular Biology, Bulgarian Academy of Sciences, Sofia.
authors.forename: K
authors.initials: K
authors.lastname: Grancharov
authors.forename: H
authors.initials: H
authors.lastname: Engelberg
authors.forename: Z
authors.initials: Z
authors.lastname: Naydenova
authors.forename: G
authors.initials: G
authors.lastname: Müller
authors.forename: A W
authors.initials: AW
authors.lastname: Rettenmeier
authors.forename: E
authors.initials: E
authors.lastname: Golovinsky
mesh_terms: 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
chemical_list: D002273:Carcinogens; D004791:Enzyme Inhibitors; D009153:Mutagens; D014453:Glucuronosyltransferase