Strain, sex and developmental profiles of cocaine metabolizing enzymes in mice

Abstract

Cocaine is a potent hepatotoxin in laboratory mice, although the cocaine-induced hepatotoxicity (CIH) is due to the action of a metabolite of cocaine. Cocaine can be hydrolyzed by serum cholinesterase (ChE) to inactive products, or be oxidized by hepatic cytochrome P-450 and FAD-containing monooxygenase (FADM). The oxidative pathway is thought to be responsible for production of the hepatotoxic metabolite of cocaine, presumably norcocaine nitroxide. Female mice are much more resistant to CIH than males of the same strain. We have found that immature male mice are as resistant as females to the development of CIH. Males did not show any CIH until the onset of puberty (30 days of age), indicating that the development of CIH in males was under hormonal control. To determine if the major cocaine-metabolizing enzymes were responsible for the regulation of CIH, we measured the activities of ChE, cocaine N-demethylation (CND) and FADM as a function of sex in C57BL/6Ibg and DBA/2Ibg mice 20–21, 30 ± 1 and 65 ± 5 days of age. There was a significant sex difference in ChE activity (females higher than males) but no effect of age. Cocaine N-demethylation increased in both males and females with age, but there was no consistent sex difference. Activity of FADM declined in males as a function of age, but remained constant in females. The lack of a consistent correlation between enzyme activities and sex-, strain-, and age-dependent differences in susceptibility to CIH, do not support a regulatory role for ChE, CND or FADM in mediating the hepatotoxic response.