THE ROLE OF CYP ENZYMES IN COCAINE-INDUCED LIVER-DAMAGE

Cocaine is hepatotoxic in several species, including man. A high dose of cocaine produces metabolism-dependent, mainly pericentral, liver da mage. At 24 h after a single dose of cocaine, mouse hepatic P450 conte nt decreases but CYP2A activities; coumarin 7-hydroxylase and testoste rone 15 alpha-hydroxylase increase concomitant with prominent diffuse cell necrosis. Repeated adminision of cocaine for up to 5 days decreas es CYA1A1/2, 2A4/5, 2Cx, and 2E1 related enzymatic activities. However , after five doses of cocaine, CYP2B10 increases in conjunction with t he healing process. In the acute phase, the increased CYP2A activities do not participate in cocaine bioactivation. CYP3A enzymes are princi pally responsible for the cocaine N-demethylation in human and mouse l iver microsomes. The hepatic metabolic CYP enzyme profile will change during prolonged cocaine intake, this being accompanied by altered cel l morphology. Possible connections to cocaine toxicity in man are disc ussed.