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 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).
Sato
G
G
Exploratory Safety Assessment Research, Eisai Co., Ltd., Tsukuba, Ibaraki, Japan. g-sato@hhc.eisai.co.jp
Aoki
T
T
Hosokawa
S
S
Sagami
F
F
Tsukidate
K
K
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*
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