title: Cocaine hepatotoxicity: influence of hepatic enzyme inducing and inhibiting agents on the site of necrosis.
abstract: Cocaine-induced hepatotoxicity has been reported in human beings and is well documented in mice. One interesting feature of this toxicity that appears to be common to both species is an apparent shift in the intraacinar site of necrosis under circumstances known to alter cocaine metabolism. However, the evidence in human subjects is limited, and studies elucidating the mechanism of this phenomenon cannot be performed in human beings. Although future studies in mice may define the basis of this mechanism, the current evidence is a somewhat fragmented composite of studies using different mouse strains and enzyme-inducing agents. Therefore a comprehensive pathologic investigation was initiated for the purpose of identifying and establishing an animal model suitable for studying this phenomenon. In naive ICR mice a single 60 mg/kg dose of cocaine was found to produce midzonal (zone 2) coagulative necrosis. In mice whose oxidative metabolism had been increased with beta-ionone or in which esterase metabolism had been inhibited by diazinon, the severity of the toxicity was increased but the intraacinar origin of the lesion did not change. However, when the oxidative microsomal metabolism of ICR mice was induced by phenobarbital or beta-naphthoflavone, the acinar zone affected was dramatically different. Phenobarbital induction produced zone 1 necrosis, whereas beta-napthoflavone induction caused necrosis in zone 3. The site of necrosis corresponded with the distribution of cocaine, and its metabolites were identified with colloidal gold-conjugated antibody probes. The results of this study suggest that the agents shifting the location of cocaine-induced hepatic necrosis alter the intraacinar site of protein binding of cocaine and its metabolites.
authors.affiliation: Department of Comparative & Experimental Pathology, J. Hillis Miller Health Science Center, Gainesville, Florida.
authors.forename: L
authors.initials: L
authors.lastname: Roth
authors.forename: R D
authors.initials: RD
authors.lastname: Harbison
authors.forename: R C
authors.initials: RC
authors.lastname: James
authors.forename: T
authors.initials: T
authors.lastname: Tobin
authors.forename: S M
authors.initials: SM
authors.lastname: Roberts
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D003042:Cocaine / Q000378:metabolism / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D008297:Male; D009336:Necrosis; D045792:Norisoprenoids; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013729:Terpenes / Q000494:pharmacology; D019324:beta-Naphthoflavone
chemical_list: D001571:Benzoflavones; D045792:Norisoprenoids; D013729:Terpenes; D019324:beta-Naphthoflavone; C008157:beta-ionone; D000410:Alanine Transaminase; D003042:Cocaine; D010634:Phenobarbital