Protection from drug-induced hepatocellular changes by pretreatment with conjugating enzyme inhibitors in rats

The present paper describes the role of conjugating enzymes in the developm ent of hepatotoxicity after administration of repeated doses of a novel mon oamine oxidase type-A (MAO-A) inhibitor, (5R)3-[2-(1S)-3-cyano-1 -hydroxypr opyl)benzothiazol-6-yl]-5-methoxymethyl-2-oxazolidinine (E2011). The effect s of pretreatment with three kinds of conjugating enzyme inhibitors on hepa tic lesions induced by E2011 were evaluated in female Sprague-Dawley rats. The inhibitors used were 2,6-dichloro-4-nitrophenol (DCNP; inhibitor of sul fotransferase (ST)), pentachlorophenol (PCP; inhibitor of both ST and acety ltransferase (AT) or ranitidine (inhibitor of UDP-glucuronosyltransferase ( UDP-GT)). Two weeks treatment of E2011 alone at an oral dosage of 150 mg/kg induced hepatocellular changes characterized by nuclear enlargement. Daily pretreatment with DCNP (10 mg/kg, i.p.) enhanced the E2011-induced hepatoc ellular changes accompanied by single cell necrosis. On the other hand, the hepatotoxicity was clearly diminished by PCP (5 mg/kg, i.p.). Ranitidine p retreatment had no effect. Protection by PCP was attributed to the inhibito ry effects of AT in addition to ST; it was considered that the hepatocellul ar changes caused by E2011 were largely dependent on the formation of acety l conjugate(s), (C) 2001 Elsevier Science Inc. All rights reserved.