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, 6 4 mg/kg), dimethylnitrosamine (DMNA, 30 mg/kg), hexachlorobutadiene (H CBD, 50 mg/kg), carbon tetrachloride (CCl4, 24 mg/kg), cocaine (60 mg/ kg) and pyrazole (300 mg/kg) on the hepatic histology and monooxygenas es in DBA/2 and C57B1/6 strains of mice were investigated. All substan ces caused histologically verified injury to the liver, which varied i n appearance and severity depending on the compound and the mouse stra in. Responses of P450-catalyzed reactions were highly dependent on the toxin and varied between different monooxygenase (MO) reactions and t wo mouse strains. In DBA/2 strain, coumarin 7-hydroxylase (COH) activi ty 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 w ere found: HCBD significantly increased T15alphaOH, PROD and EROD acti vities in C57B1/6 mice, whereas cocaine caused a significant stimulati on of T15alphaOH and PROD in DBA/2 mice, It is concluded that i) diffe rent hepatoxins cause different types of liver injury and responses of the monooxygenase complex (''hepatotoxin-specific finger prints''), i i) although DBA/2 and C57B1/6 mice responded rather similarly to hepat otoxins, also with respect to P450 content and most MO activities, the y displayed a profound difference in the behaviour of COH activity, an d iii) within the P450 superfamily, the regulation of COH activity see ms to be rather unique, also when compared to its structurally close e nzyme, testosterone 15alpha-hydroxylase.