Effect of cimetidine on hepatic biochemical changes, liver toxicity and major urinary metabolite excretion of trichloroethylene in rats.
The effects of cimetidine (CIM) (an inhibitor of the hepatic microsomal monooxygenase system) on the metabolism and hepatotoxicity of trichloroethylene (TRI) were studied in male Sprague-Dawley rats. Rats were given three doses of 120 mg/kg i.p. (low-dose regimen) of CIM at 0, 6 and 11 h for 1 day, or ten doses of 200 mg/kg (high-dose regimen) at 8, 11, 14 and 17 h for 2 days and 8 and 11 h on 3rd day. Trichloroethylene (0.5 or 0.65 ml/kg) was administered i.p. 1 h after 2nd dose (low-dose regimen) or 9th dose (high-dose regimen) of CIM. In the low-dose regimen study, the activity of hepatic microsomal aminopyrine N-demethylase was decreased 1 and 5 h after the second dose and 7 h after the third dose of CIM, but became normal 20 h after the last dose. The cytochrome P-450 content and the activities of aniline hydroxylase and epoxide hydratase remained unchanged. Trichloroethylene at both dose levels produced liver toxicity, as verified by increase in activities of SDH and SGPT as well as by liver histology. Cimetidine alone had no such effect. An apparent reduction in TRI toxicity by CIM (at both dose regimens) could be observed histologically. The biochemical tests (SDH and SGPT) corroborated the histological changes only when TRI was given at a dose of 0.5 ml/kg combined with a high-dose regimen of CIM. Cimetidine at both dose regimens had a tendency to decrease the in vivo metabolism of TRI.(ABSTRACT TRUNCATED AT 250 WORDS)
Landriault
H
H
Faculté de Pharmacie, Université de Montréal, Québec, Canada.
Sirois
G
G
Chakrabarti
S
S
Cote
M G
MG
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001711:Biotransformation; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002927:Cimetidine / Q000494:pharmacology*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000648:ultrastructure; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013385:Succinate Dehydrogenase / Q000378:metabolism; D014241:Trichloroethylene / Q000506:poisoning* / Q000652:urine
D014241:Trichloroethylene; D002927:Cimetidine; D013385:Succinate Dehydrogenase; D000410:Alanine Transaminase