Halothane hepatotoxicity in Fischer 344 rats pretreated with isoniazid.
Male Fischer 344 rats were used to investigate the hepatic effects of exposure to halothane under normoxic conditions (FIO2 = 0.21) in isoniazid-treated rats. Animals were treated with saline or isoniazid (50 mg/kg) for 7 days and then were exposed to either 1% halothane or air for 2 hr. One-half of the rats from each treatment and exposure group were killed 24 hr postexposure; the remaining were killed 4 days postexposure. Twenty-four hours following halothane exposure, serum transaminase levels were significantly elevated in isoniazid- compared with saline-treated rats (i.e., aspartate aminotransferase = twofold; alanine aminotransferase = seven-fold). Cholesterol levels were significantly depressed by halothane exposure in both saline- and isoniazid-treated rats. Other serum parameters indicative of hepatic and renal function were not different: alkaline phosphatase, total protein, total bilirubin, hematocrit, uric acid, creatinine, urea nitrogen, Na+, K+, Ca2+, and inorganic phosphate. Neither saline-treated nor isoniazid-treated rats exposed to air exhibited histologic evidence of hepatic damage. Halothane-exposed rats, however, showed a circumscribed disruption of cellular morphology. The most severe lesions were observed with isoniazid-treated animals with extensive pericentral hepatocellular necrosis and infiltration by leucocytes and Kupffer cells. Serum concentrations of two products of the oxidative metabolism of halothane, trifluoroacetic acid and bromide, were significantly elevated in isoniazid- compared with saline-treated rats. Serum levels of fluoride, a product of reductive metabolism, were not different. These results strongly suggest that hepatic injury following halothane administration can be produced by intermediates of oxidative metabolism.
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001835:Body Weight / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D006221:Halothane / Q000378:metabolism / Q000633:toxicity*; D007538:Isoniazid / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D014284:Triiodothyronine / Q000494:pharmacology
D014284:Triiodothyronine; D003577:Cytochrome P-450 Enzyme System; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D010100:Oxygen; D006221:Halothane; D007538:Isoniazid