title: Cytochrome P450 1A1 (CYP1A1) inhibitor alpha-naphthoflavone interferes with UDP-glucuronosyltransferase (UGT) activity in intact but not in permeabilized hepatic microsomes from 3-methylcholanthrene-treated rats: possible involvement of UGT-P450 interactions.
abstract: The effects of cytochrome P450 (P450, CYP) ligands and permeabilization of microsomes on 3-hydroxybenzo(a)pyrene [3-OH-B(a)P] glucuronidation mediated by rat hepatic microsomes were studied. While the UDP-glucuronosyltransferase (UGT) activity with non-permeabilized microsomes from 3-methylcholanthrene (MC)-treated rats was markedly reduced by alpha-naphthoflavone (NF), this inhibitor had hardly any effect when permeabilized microsomes were used in which the inhibitor was expected to have easy access to UGT. Kinetic analysis indicated that the inhibitory effect of alpha-NF is competitive. These results suggest that a UGT isoform(s) involved in 3-OH-B(a)P glucuronidation is interfered by a CYP1A inhibitor via a mechanism dependent on the intact nature of microsomal membranes in MC-treated rats. It is likely that P450 functions as a substrate transporter for some isoforms of UGT via possible interactions between UGT and P450.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Taura
authors.forename: Eri
authors.initials: E
authors.lastname: Naito
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishii
authors.forename: Masa-aki
authors.initials: MA
authors.lastname: Mori
authors.forename: Kazuta
authors.initials: K
authors.lastname: Oguri
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yamada
mesh_terms: D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology*; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors*; D066298:In Vitro Techniques; D007700:Kinetics; D008748:Methylcholanthrene / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D010539:Permeability; D051381:Rats
chemical_list: D001571:Benzoflavones; D004791:Enzyme Inhibitors; D008748:Methylcholanthrene; C011512:alpha-naphthoflavone; D019363:Cytochrome P-450 CYP1A1; D014453:Glucuronosyltransferase