Assessment of catechol induction and glucuronidation in rat liver microsomes.
Catechols are substances with a 1,2-dihydroxybenzene group from natural or synthetic origin. The aim of this study was to determine whether catechols (4-methylcatechol, 4-nitrocatechol, 2,3-dihydroxynaphthalene) and the antiparkinsonian drugs, entacapone and tolcapone, at doses 150 to 300 mg/kg/day, for 3 days, are able to enhance their own glucuronidation. The induction potency of catechols on rat liver UDP-glucuronosyltransferases (UGTs) was compared with that of a standard polychlorinated biphenyl (PCB) inducer, Aroclor 1254. The glucuronidation rate of these catechols was enhanced up to 15-fold in the liver microsomes of PCB-treated rats, whereas treatment with catechols had little effect. Entacapone, tolcapone, 4-methylcatechol, catechol, 2,3-dihydroxynaphthalene, and 4-nitrocatechol were glucuronidated in control microsomes at rates ranging from 0.12 for entacapone to 22.0 nmol/min/mg for 4-nitrocatechol. Using 1-naphthol, entacapone, and 1-hydroxypyrene as substrates, a 5-, 8-, and 16-fold induction was detected in the PCB rats, respectively, whereas the catechol-induced activities were 1.1- to 1.5-fold only. Entacapone was glucuronidated more efficiently by PCB microsomes than by control microsomes (Vmax/Km, 0.0125 and 0.0016 ml/min/mg protein, respectively). Similar kinetic results were obtained for 1-hydroxypyrene. The Eadie-Hofstee plots suggested the contribution of multiple UGTs for the glucuronidation of 1-hydroxypyrene (Km1, Km2, Km3 = 0.8, 9.7, and 63 microM, and Vmax1, Vmax2, Vmax3 = 11, 24, and 55 nmol/min/mg, respectively), whereas only one UGT could be implicated in the glucuronidation of entacapone (Km = 130 microM, Vmax = 1.6 nmol/min/mg). In conclusion, catechols are poor inducers of their own glucuronidation supported by several UGT isoforms. Their administration is unlikely to affect the glucuronidation of other drugs administered concomitantly.
Elovaara
Eivor
E
Department of Industrial Hygiene and Toxicology, Finnish Institute of Occupational Health, FIN-00250 Helsinki, Finland. Eivor.Elovaara@occuphealth.fi
Mikkola
Jouni
J
Luukkanen
Leena
L
Antonio
Laurence
L
Fournel-Gigleux
Sylvie
S
Burchell
Brian
B
Magdalou
Jacques
J
Taskinen
Jyrki
J
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D002396:Catechols / Q000378:metabolism* / Q000494:pharmacology; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020719:Glucuronides / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000378:metabolism; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D008111:Liver Function Tests; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D009284:Naphthols / Q000378:metabolism; D009570:Nitriles; D011078:Polychlorinated Biphenyls / Q000494:pharmacology; D011721:Pyrenes / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D002396:Catechols; D004791:Enzyme Inhibitors; D020719:Glucuronides; D007527:Isoenzymes; D009284:Naphthols; D009570:Nitriles; D011721:Pyrenes; C029350:1-naphthol; C071192:entacapone; D011078:Polychlorinated Biphenyls; D014453:Glucuronosyltransferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; C033146:1-hydroxypyrene