Sex and strain differences in the hepatotoxic response to acute cocaine administration in the mouse.
Cocaine-induced hepatotoxicity was examined in vivo in a dose-responsive manner in C57BL/6Ibg, DBA/2Ibg, C3H/2Ibg, and Balb/cJ mice. Serum glutamic-pyruvic transaminase (SGPT) activities were determined 24 hours after intraperitoneal (IP) administration of cocaine (20 to 100 mg/kg). Significant elevations (100- to 150-fold) in SGPT were observed in male mice receiving cocaine. Significant differences in sensitivity to cocaine-induced hepatotoxicity were found among males of the inbred strains, with Balb being most sensitive and C57BL being least sensitive and C3H and DBA strains exhibiting intermediate sensitivity. Female mice of the four inbred strains were more resistant than males to cocaine-mediated hepatotoxicity, as indicated by only twofold to tenfold elevations in SGPT values. Among the females, sensitivity of the four inbred strains--as indicated by dose response curves--fell into two categories: the sensitive strains (C3H and C57BL) and the resistant strains (Balb and DBA). Pretreatment of males of the four inbred strains with the P-450 inducer phenobarbital resulted in enhancement of cocaine-mediated hepatotoxicity in the C57BL and Balb but not the C3H and DBA mice. Phenobarbital pretreatment of females of the four inbred strains resulted in enhancement of the hepatotoxic response to cocaine in the C3H, DBA, and Balb mice. Phenobarbital-pretreated C57BL females exhibited a 100% mortality rate after the acute cocaine dose, and thus no determination of hepatotoxicity could be established for them. These data demonstrate sex and strain differences in cocaine-induced hepatotoxicity and suggest that phenobarbital pretreatment does not uniformly enhance the hepatotoxicity of cocaine.
Boyer
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CS
Molecular and Environmental Toxicology Program, University of Colorado Health Sciences Center, Denver 80262.
Ross
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Petersen
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DR
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000378:metabolism*; D003042:Cocaine / Q000008:administration & dosage / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004790:Enzyme Induction; D005260:Female; D008297:Male; D051379:Mice; D010634:Phenobarbital / Q000494:pharmacology; D012737:Sex Factors; D013045:Species Specificity
D003577:Cytochrome P-450 Enzyme System; D000410:Alanine Transaminase; D003042:Cocaine; D010634:Phenobarbital