Subacute cocaine treatment changes expression of mouse liver cytochrome P450 isoforms

Acute administration of single high doses of cocaine (50 or 60 mg/kg) produ ces liver injury in mice that have been pretreated with inducers of mixed f unction oxidases. Multiple low doses of cocaine (10-30 mg/kg) will produce hepatotoxicity without prior induction. To establish whether cocaine can in duce its own activation, mice were given three daily injections of cocaine. Total cytochrome P450 content of the liver did not change. After 3 days th e amount of cytochrome P450 2B10, as measured by pentoxy resorufin-O-dealky lase activity and immunoblotting, increased 3-fold. Cytochrome P450 2A5-cat alyzed coumarin 7-hydroxylase activity and immunoreactive protein increased by about 50%. Enzyme activities and Western blotting of isoforms 1A, 2E, a nd 3A showed no change during this time. Chronic cocaine increased N-hydrox ylation of norcocaine. Immunoinhibition studies showed that cytochrome P450 2A5 was the major isoform responsible for norcocaine N-hydroxylation. Thes e results demonstrate that chronic cocaine can induce its own metabolism. S imilar increases were also observed in mice not susceptible to liver injury from chronic cocaine.