COCAINE HEPATOTOXICITY - A STUDY AN THE PATHOGENESIS OF PERIPORTAL NECROSIS

Cocaine is reported to produce either periportal or mid-zonal necrosis in mice pretreated with the enzyme inducer phenobarbitone (James ef a l. 1987; Powell et al. 1991, Charles and Powell 1992). Dose-response a nd time course experiments were performed in phenobarbitone treated ma le DBA/2Ha mice to study the pathogenesis of this unusual cocaine indu ced lesion. An increase in the dose of cocaine from 60 to 90 or 120 mg /kg produced more extensive and severe periportal and linking portal d amage and elevated plasma aspartate (AST) and alanine (ALT) aminotrans ferases in a dose dependent manner. Scattered hepatocyte degeneration began at the edge of the periportal region and was detectable by elect ron microscopy within 30 minutes of administration of 60 mg/kg of coca ine, with conspicuous disorganization of the endoplasmic reticulum bei ng one of the earliest changes. Significant elevations of plasma AST a nd ALT were observed 3 hours after cocaine administration and were sus tained for 12 hours, at which time progressive hepatocyte damage had d eveloped into a network of confluent necrosis at the periphery of the periportal region. The rapidity of organelle derangement and subsequen t cell death, and absence of any effect on total cytochrome P-450 or F AD-mono-oxygenase levels, appear to distinguish this periportal lesion from previous reports of cocaine induced centrilobular necrosis in no n-enzyme induced mice, suggesting that the two types of damage may dev elop by different mechanisms. The observation that periportal lesions commence at the periphery of the periportal area, progressing portalwa rds with increasing dose and time, offers an explanation for the previ ously conflicting reports of cocaine induced mid-zonal and/or periport al lesions in phenobarbitone treated mice.