Comparison of covalent binding from halothane metabolism in hepatic microsomes from phenobarbital-induced and hyperthyroid rats.
1. Hepatic microsomal suspensions from rats pretreated with saline, phenobarbital or triiodothyronine were incubated with 14C-halothane under aerobic and anerobic conditions. 2. Metabolism of halothane by microsomes from phenobarbital-induced rats under anaerobic conditions resulted in covalent binding of 14C to microsomal lipids, and to a lesser extent, microsomal proteins, as seen in previous studies. Covalent binding was decreased with incubation under aerobic conditions. 3. Metabolism of halothane by microsomal suspensions from hyperthyroid rats produced much less covalent binding to microsomal lipids and proteins, with binding similar to, or less than, that observed with microsomes from saline-treated rats. The covalent binding of halothane to protein of microsomes from hyperthyroid rats was dependent upon metabolism, and was inhibited by SKF 525A, reduced glutathione, or cytosol. 4. The in vitro observations with respect to covalent binding are inconsistent with previous reports on halothane hepatotoxicity in hyperthyroid rats in vivo. This inconsistency and the relatively small extent of covalent binding with microsomes from hyperthyroid rats observed, suggests that covalent binding is not an important mechanism of halothane hepatotoxicity in the hyperthyroid rat model.
Smith
A C
AC
National Cancer Institute, Bethesda, MD.
Roberts
S M
SM
James
R C
RC
Berman
L M
LM
Harbison
R D
RD
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D005978:Glutathione / Q000494:pharmacology; D006221:Halothane / Q000378:metabolism* / Q000633:toxicity; D006980:Hyperthyroidism / Q000139:chemically induced / Q000378:metabolism*; D050356:Lipid Metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D009249:NADP / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology*; D011506:Proteins / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D014284:Triiodothyronine
D011506:Proteins; D011725:Pyridines; D014284:Triiodothyronine; C013109:metapyrone; D009249:NADP; D005978:Glutathione; D006221:Halothane; D010634:Phenobarbital