Developmental expression of cocaine hepatotoxicity in the mouse

Cocaine may be metabolized either by ester hydrolysis to inactive products or by oxidation via a cytochrome P-450 and FAD-monooxygenase pathway to a hepatotoxic metabolite, presumably norcocaine nitroxide. Mice are the species most susceptible to cocaine-induced hepatotoxicity (CIH), and marked strain differences in response have been found. Female mice are very resistant to CIH, whereas males are susceptible, indicating that hormonal factors may be involved. We treated mice of 5 inbred strains with cocaine at three ages: 20 days (weanling), 30 days (adolescent) and 60 days (adult). The CIH response was assessed by measurement of plasma alanine aminotransferase (ALT) activity 18 hours later. For each of the strains females of all three age groups were resistant to CIH, and males did not begin to develop CIH until approximately 30 days of age. The degree of CIH in 30-day-old males was intermediate between the levels found in 20-day-old males and adult males. These data suggest that the enzyme, or enzymes, responsible for the production of the toxic metabolite are absent, or at very low levels, in female and immature male mice, and that they are either inducible by androgens or are repressed by estrogens or progestins. It is possible that these enzymes may be involved in the production of toxic metabolites of compounds other than cocaine.