Cocaine hepatotoxicity: a study on 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 et al. 1987; Powell et al. 1991; Charles & Powell 1992). Dose-response and time course experiments were performed in phenobarbitone treated male DBA/2Ha mice to study the pathogenesis of this unusual cocaine induced 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 damage and elevated plasma aspartate (AST) and alanine (ALT) aminotransferases in a dose dependent manner. Scattered hepatocyte degeneration began at the edge of the periportal region and was detectable by electron microscopy within 30 minutes of administration of 60 mg/kg of cocaine, with conspicuous disorganization of the endoplasmic reticulum being one of the earliest changes. Significant elevations of plasma AST and ALT were observed 3 hours after cocaine administration and were sustained for 12 hours, at which time progressive hepatocyte damage had developed into a network of confluent necrosis at the periphery of the periportal region. The rapidity of organelle derangement and subsequent cell death, and absence of any effect on total cytochrome P-450 or FAD-mono-oxygenase levels, appear to distinguish this periportal lesion from previous reports of cocaine induced centrilobular necrosis in non-enzyme induced mice, suggesting that the two types of damage may develop by different mechanisms. The observation that periportal lesions commence at the periphery of the periportal area, progressing portalwards with increasing dose and time, offers an explanation for the previously conflicting reports of cocaine induced mid-zonal and/or periportal lesions in phenobarbitone treated mice.
Powell
C J
CJ
DH Department of Toxicology, St. Bartholomew's Hospital Medical College, London, UK.
Charles
S J
SJ
Mullervy
J
J
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D003042:Cocaine / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000187:drug effects* / Q000473:pathology* / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008854:Microscopy, Electron; D009336:Necrosis; D013997:Time Factors
D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D003042:Cocaine