Effects of H2 receptor antagonists on the hepatotoxicity of various chemicals.
H2 receptor antagonist-hepatotoxicant interactions were evaluated in male Fischer-344 rats. The H2 receptor antagonists, cimetidine, ranitidine, oxmetidine, and 2-[2-(2-dimethyl-aminomethyl-5-furanylmethyl-thio)-ethylamino]-5-( 6-methyl- 3-picolyl)-4-pyrimidine trihydrohydrochloride (SK&F 93479) were administered (p.o.) at a dose of 0.143 mMoles/kg 30 minutes prior to hepatotoxicant treatment. Submaximal hepatotoxic doses (p.o.) of carbon tetrachloride (795 mg/kg), bromobenzene (748 mg/kg), chloroform (1,190 mg/kg), allyl alcohol (60 mg/kg), galactosamine (200 mg/kg, i.p.), and acetaminophen (1000 mg/kg) were employed. Hepatotoxicity was evaluated by determining serum alanine aminotransferase activity (ALT). Pretreatment with the H2 receptor antagonists did not significantly alter carbon tetrachloride or allyl alcohol hepatotoxicity. Bromobenzene and chloroform toxicities were unaffected by cimetidine, ranitidine, and oxmetidine pretreatment but were potentiated by SK&F 93479. Cimetidine and ranitidine decreased galactosamine mediated hepatotoxicity. Acetaminophen hepatotoxicity was markedly potentiated by ranitidine pretreatment but was unaltered by the other three H2 receptor antagonists. The mechanisms of hepatotoxicity potentiation or protection have not been determined, however, the lack of consistent H2 receptor antagonists effects indicates that it is unlikely that alterations in G.I. pH account for the effects observed. H2 receptor antagonist mediated changes in hepatotoxicant metabolism provide a more plausible mechanism of action, particularly in the cases of SK&F 93479 potentiation of bromobenzene and chloroform and ranitidine potentiation of acetaminophen hepatotoxicity.
D000433:1-Propanol / Q000633:toxicity; D000082:Acetaminophen / Q000633:toxicity; D000818:Animals; D001969:Bromobenzenes / Q000633:toxicity; D002252:Carbon Tetrachloride Poisoning; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D002725:Chloroform / Q000633:toxicity; D002927:Cimetidine / Q000494:pharmacology; D004336:Drug Antagonism; D004357:Drug Synergism; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D008099:Liver / Q000187:drug effects; D008297:Male; D020005:Propanols; D011744:Pyrimidinones / Q000494:pharmacology; D011899:Ranitidine / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344
D001969:Bromobenzenes; D006635:Histamine H2 Antagonists; D007093:Imidazoles; D020005:Propanols; D011744:Pyrimidinones; D000082:Acetaminophen; C006463:allyl alcohol; C033275:SK&F 93479; D002725:Chloroform; D002927:Cimetidine; D011899:Ranitidine; D000433:1-Propanol; C032036:bromobenzene; C027703:oxmetidine