Modification of hepatic cytochrome P450 profile by cocaine-induced hepatotoxicity in DBA/2 mouse.
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.(ABSTRACT TRUNCATED AT 250 WORDS)
Pellinen
P
P
Department of Pharmacology and Toxicology, University of Kuopio, Finland.
Stenbäck
F
F
Raunio
H
H
Pelkonen
O
O
Pasanen
M
M
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D056486:Chemical and Drug Induced Liver Injury; D003042:Cocaine / Q000633:toxicity*; D065637:Cytochrome P-450 CYP2A6; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000187:drug effects* / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D008099:Liver / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D008107:Liver Diseases / Q000201:enzymology* / Q000473:pathology; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008862:Microsomes, Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D013997:Time Factors
D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585520:Cyp2a5 protein, mouse; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2; D003042:Cocaine