Response of mouse liver coumarin 7-hydroxylase activity to hepatotoxins: dependence on strain and agent and comparison to other monooxygenases.
Acute effects of a single intraperitoneal dose of allyl alcohol (AA, 64 mg/kg), dimethylnitrosamine (DMNA, 30 mg/kg), hexachlorobutadiene (HCBD, 50 mg/kg), carbon tetrachloride (CCl4, 24 mg/kg), cocaine (60 mg/kg) and pyrazole (300 mg/kg) on the hepatic histology and monooxygenases in DBA/2 and C57Bl/6 strains of mice were investigated. All substances caused histologically verified injury to the liver, which varied in appearance and severity depending on the compound and the mouse strain. Responses of P450-catalyzed reactions were highly dependent on the toxin and varied between different monooxygenase (MO) reactions and two mouse strains. In DBA/2 strain, coumarin 7-hydroxylase (COH) activity was increased from 3- to 5-fold by pyrazole, cocaine, HCBD and CCl4. With respect to P450 content and other MO activities, no changes or even decreases were generally observed. Some exceptions to this rule were found: HCBD significantly increased T15 alpha OH, PROD and EROD activities in C57Bl/6 mice, whereas cocaine caused a significant stimulation of T15 alpha OH and PROD in DBA/2 mice, It is concluded that i) different hepatoxins cause different types of liver injury and responses of the monooxygenase complex ("hepatotoxinspecific finger prints"), ii) although DBA/2 and C57Bl/6 mice responded rather similarly to hepatotoxins, also with respect to P450 content and most MO activities, they displayed a profound difference in the behaviour of COH activity, and iii) within the P450 superfamily, the regulation of COH activity seems to be rather unique, also when compared to its structurally close enzyme, testosterone 15 alpha-hydroxylase.
Pellinen
P
P
Department of Pharmacology and Toxicology, University of Kuopio, Finland.
Stenbäck
F
F
Rautio
A
A
Pelkonen
O
O
Lang
M
M
Pasanen
M
M
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D015153:Blotting, Western; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology* / Q000473:pathology; D065637:Cytochrome P-450 CYP2A6; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006651:Histocytochemistry; D008099:Liver / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008862:Microsomes, Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D013045:Species Specificity; D013250:Steroid Hydroxylases / Q000378:metabolism
D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D065637:Cytochrome P-450 CYP2A6; C050356:steroid 15-alpha-hydroxylase