Role of biotransformation in the potentiation of halocarbon hepatotoxicity by 2,5‐hexanedione

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Abstract
2,5‐Hexanedione (2,5‐HD) pretreatment potentiated CHCl 3 ‐induced hepatotoxicity. 2,5‐HD significantly increased hepatic cytochrome P‐450, NADPH cytochrome c reductase, aniline hydroxylation, p‐nitroanisole O‐demethylation, and aminopyrine N‐demethylation in both male and female mice. 2,5‐HD pretreatment potentiated CHCl 3 ‐induced centrilobular necrosis and increased serum alanine amino transferase (ALT) activity by 20 times more than CHCl 3 alone. Similarly, 2,5‐HD pretreatment potentiated CDCl 3 ‐induced hepatotoxicity as well as CCl 4 ‐induced hepatotoxicity in male mice, but did not potentiate trichloroethylene‐, 1,1,2‐trichloroethane‐, or perchloroethylene‐induced hepatotoxicity. In female mice, 2,5‐HD pretreatment potentiated CHCl 3 ‐ and CDCl 3 ‐induced hepatotoxicity as well as trichloroethylene‐, 1,1,2‐trichloroethane‐, and carbon tetrachloride‐induced hepatotoxicity, but not perchloroethylene‐induced hepatotoxicity. 2,5‐HD pretreatment had no preferential effect on either CHCl 3 ‐ or CDCl 3 ‐induced hepatotoxicity in females. However, phenobarbital pretreatment did differentiate CHCl 3 ‐ and CDCl 3 ‐induced hepatotoxicity in females. 2,5‐HD‐induced potentiation of halocarbon hepatotoxicity is sex dependent.