title: Protection from drug-induced hepatocellular changes by pretreatment with conjugating enzyme inhibitors in rats.
abstract: The present paper describes the role of conjugating enzymes in the development of hepatotoxicity after administration of repeated doses of a novel monoamine oxidase type-A (MAO-A) inhibitor, (5R)-3-[2-(( 1S)-3-cyano-1-hydroxypropyl)benzothiazol-6-yl]-5-methoxymethyl-2-oxazolidinone (E2011). The effects of pretreatment with three kinds of conjugating enzyme inhibitors on hepatic lesions induced by E2011 were evaluated in female Sprague-Dawley rats. The inhibitors used were 2,6-dichloro-4-nitrophenol (DCNP; inhibitor of sulfotransferase (ST)), pentachlorophenol (PCP; inhibitor of both ST and acetyltransferase (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 hepatocellular changes accompanied by single cell necrosis. On the other hand, the hepatotoxicity was clearly diminished by PCP (5 mg/kg, i.p.). Ranitidine pretreatment had no effect. Protection by PCP was attributed to the inhibitory effects of AT in addition to ST; it was considered that the hepatocellular changes caused by E2011 were largely dependent on the formation of acetyl conjugate(s).
authors.affiliation: Exploratory Safety Assessment Research, Eisai Co., Ltd., Tsukuba, Ibaraki, Japan. g-sato@hhc.eisai.co.jp
authors.forename: G
authors.initials: G
authors.lastname: Sato
authors.forename: T
authors.initials: T
authors.lastname: Aoki
authors.forename: S
authors.initials: S
authors.lastname: Hosokawa
authors.forename: F
authors.initials: F
authors.lastname: Sagami
authors.forename: K
authors.initials: K
authors.lastname: Tsukidate
mesh_terms: D000123:Acetyltransferases / Q000037:antagonists & inhibitors; D000818:Animals; D052160:Benzothiazoles; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008996:Monoamine Oxidase Inhibitors / Q000633:toxicity*; D009596:Nitrophenols / Q000494:pharmacology*; D023303:Oxazolidinones / Q000378:metabolism / Q000633:toxicity*; D010416:Pentachlorophenol / Q000494:pharmacology*; D011899:Ranitidine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015238:Sulfotransferases / Q000037:antagonists & inhibitors; D013844:Thiazoles / Q000378:metabolism / Q000633:toxicity*
chemical_list: D052160:Benzothiazoles; C091708:E 2011; D004791:Enzyme Inhibitors; D008996:Monoamine Oxidase Inhibitors; D009596:Nitrophenols; D023303:Oxazolidinones; D013844:Thiazoles; C015802:2,6-dichloro-4-nitrophenol; D011899:Ranitidine; D010416:Pentachlorophenol; D000123:Acetyltransferases; D014453:Glucuronosyltransferase; D015238:Sulfotransferases