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Drug Metabolism and Disposition Fast Forward
First published on September 15, 2004; DOI: 10.1124/dmd.104.000992

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Received for publication June 18, 2004.
Revised September 10, 2004.
Accepted for publication September 13, 2004.

ASSESSMENT OF CATECHOL INDUCTION AND GLUCURONIDATION IN RAT LIVER MICROSOMES

Eivor Elovaara 1*, Jouni Mikkola 1, Leena Luukkanen 2, Laurence Antonio 3, Sylvie Fournel-Gigleux 3, Brian Burchell 4, Jacques Magdalou 5, Jyrki Taskinen 2

1 Finnish Institute of Occupational Health 2 Univeristy of Helsinki 3 CRNS-Universite Henri Poincare Nancy 1 4 University of Dundee 5 CNRS-Universite Henri Poincare Nancy I

* Address correspondence to: E-mail: eivor.elovaara{at}occuphealth.fi

Abstract

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 (UGT) was compared with that of a standard polychlorinated biphenyl (PCB) inducer, Aroclor 1254. 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 1.1-1.5-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, 63 µM, and Vmax1, Vmax2, Vmax3= 11, 24, 55 nmol/min/mg, respectively), whereas only one UGT could be implicated in the glucuronidation of entacapone (Km=130 µM, 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.


Key words: drug disposition, drug interactions, drug-induced hepatotoxicity, enzyme induction, enzyme kinetics, glucuronidation, liver microsomes, phase II drug metabolism, polycyclic aromatic hydrocarbons, UDP glucuronyltransferases




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