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ASSESSMENT OF CATECHOL INDUCTION AND GLUCURONIDATION IN RAT LIVER MICROSOMES

Laboratory of Toxicokinetics and Metabolism, Department of Industrial Hygiene and Toxicology, Finnish Institute of Occupational Health, Helsinki, Finland (E.E., J.M., L.L.); Viikki Drug Discovery Technology Center, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland (J.T.); UMR 7561 Centre National de la Research Scientifique-Université Henri Poincaré Nancy, Vandoeuvre-lès-Nancy, France (L.A., S.F.-G., J.M.); and Department of Molecular and Cellular Pathology, Ninewells Hospital and Medical School, University of Dundee, Dundee United Kingdom (B.B.)

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 (V_max/K_m, 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 (K_m1, K_m2, K_m3 = 0.8, 9.7, and 63 µM, and V_max1, V_max2, V_max3 = 11, 24, and 55 nmol/min/mg, respectively), whereas only one UGT could be implicated in the glucuronidation of entacapone (K_m = 130 µM, V_max = 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.