Halothane-induced liver injury as a consequence of enhanced microsomal lipid peroxidation in guinea pigs.
We investigated the role of microsomal lipid peroxidation in halothane hepatotoxicity in guinea pigs. Animals were exposed to halothane, isoflurane or enflurane. Enhancement of microsomal lipid peroxidation was specific to halothane. The time-course of lipid peroxidation and hepatic damage following a single exposure to halothane was investigated by measuring the thiobarbituric acid (TBA)reactive products, serum transaminase activity, reduced glutathione (GSH) concentration and histopathological examination. Microsomal lipid peroxidation was enhanced most rapidly and preceded GSH depletion and hepatic injury. Metyrapone, an inhibitor of cytochrome P-450, and N-tert-butyl-alpha-phenylnitrone (BPN), a radical trapping agent, inhibited halothane-induced lipid peroxidation and the incidence and severity of liver injury. The metabolism of halothane was considered to be inhibited by metyrapone and the reactivity of radical intermediates was considered to be decreased by BPN. Microsomal lipid peroxidation was initiated by radical metabolites of halothane but did not result from GSH depletion. Inhibition of microsomal lipid peroxidation reduced the halothane hepatotoxicity. These results demonstrated that the halothane-induced liver injury was caused by microsomal lipid peroxidation in guinea pigs.
Akita
S
S
Division of Dental Anesthesia, Hiroshima University Dental Hospital, Japan.
Morio
M
M
Kawahara
M
M
Takeshita
T
T
Fujii
K
K
Yamamoto
M
M
D000280:Administration, Inhalation; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006168:Guinea Pigs; D006221:Halothane / Q000009:adverse effects*; D008054:Lipid Peroxides / Q000378:metabolism*; D008099:Liver / Q000187:drug effects*; D008297:Male; D008797:Metyrapone / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D051381:Rats; D000637:Transaminases / Q000378:metabolism
D008054:Lipid Peroxides; D000637:Transaminases; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D005978:Glutathione; D006221:Halothane; D008797:Metyrapone