Modification of hepatic cytochrome P450 profile by cocaine-induced hepatotoxicity in DBA/2 mouse

Abstract

Previous studies in our laboratory have shown that a hepatotoxic dose of cocaine increases coumarin 7-hydroxylase activity in male DBA/2 mouse liver. In the present study, the dose- and time-dependent responses of the hepatic CYP2A4/5 complex to cocaine-induced liver damage were studied. Cocaine increased CYP2A4/5 levels in a dose-dependent manner. The maximal increases in coumarin 7-hydroxylase activity (4-fold), microsomal CYP2A4/5 content (3-fold) and steady-state mRNA levels (10-fold) were observed at 24 h after administration of a single dose of 60 mg/kg cocaine coinciding with morphologically detectable diffuse liver damage, while the total P450 content was not changed. 3 and 5 days after the daily administration of cocaine severe, mainly pericentral (zone III of Rappaport), liver damage was apparent in parallel with a clear decline in CYP2A4/5 mRNA, protein content and coumarin 7-hydroxylase activity. After 5 days of treatment, CYP2A5 still remained at a very low level but an induction in CYP2B10 protein and related pentoxyresorufin O-dealkylase activity was observed. No marked changes in microsomal CYP2Cx and CYP1A1/2 contents or associated activities were observed. Dimethylnitrosamine N-demethylase activity, a marker for CYP2E1, decreased in parallel with increased cocaine dose and time and the severity of liver damage. Our results demonstrate that (i) administration of cocaine causes a clear but transient increase in the expression of Cyp2a-4/5 gene complex prior to overt liver damage and (ii) microsomal CYP2B10 and related 7-pentoxyresorufin O-dealkylase activity is markedly increased in animals treated for 5 days with cocaine concomitantly with the decrease in other monooxygenases indicating an association of coumarin 7-hydroxylase activity with liver injury and different roles for coumarin 7-hydroxylase and 7-pentoxyresorufin O-dealkylase activities in cocaine hepatotoxicity.