Subacute cocaine treatment changes expression of mouse liver cytochrome P450 isoforms.
Acute administration of single high doses of cocaine (50 or 60 mg/kg) produces liver injury in mice that have been pretreated with inducers of mixed function oxidases. Multiple low doses of cocaine (10-30 mg/kg) will produce hepatotoxicity without prior induction. To establish whether cocaine can induce its own activation, mice were given three daily injections of cocaine. Total cytochrome P450 content of the liver did not change. After 3 days the amount of cytochrome P450 2B10, as measured by pentoxy resorufin-O-dealkylase activity and immunoblotting, increased 3-fold. Cytochrome P450 2A5-catalyzed coumarin 7-hydroxylase activity and immunoreactive protein increased by about 50%. Enzyme activities and Western blotting of isoforms 1A, 2E, and 3A showed no change during this time. Chronic cocaine increased N-hydroxylation of norcocaine. Immunoinhibition studies showed that cytochrome P450 2A5 was the major isoform responsible for norcocaine N-hydroxylation. These results demonstrate that chronic cocaine can induce its own metabolism. Similar increases were also observed in mice not susceptible to liver injury from chronic cocaine.
Powers
J F
JF
Department of Pharmacology, Tufts University School of Medicine, Boston, Mass 02111, USA.
Shuster
L
L
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D003042:Cocaine / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000633:toxicity*; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008107:Liver Diseases / Q000378:metabolism; D008111:Liver Function Tests; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D017208:Rats, Wistar
D018765:Dopamine Uptake Inhibitors; D007527:Isoenzymes; D003577:Cytochrome P-450 Enzyme System; D003042:Cocaine