, Volume 348, Issue 4, pp 435-443

Response of mouse liver coumarin 7-hydroxylase activity to hepatotoxins: dependence on strain and agent and comparison to other monooxygenases

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Summary

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 C57B1/6 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 T15αOH, PROD and EROD activities in C57B1/6 mice, whereas cocaine caused a significant stimulation of Tl5αOH 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 (“hepatotoxin-specific finger prints”), (ii) although DBA/2 and C57B1/6 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 15α-hydroxylase.

An update list and suggested nomenclature of the sequenced P450 genes has been published recently (Nelson et al., DNA Cell Biol 12:1–51, 1993). The suggested nomenclature is followed in this manuscript. The murine P450Coh is the product of the Cyp2a-5 gene (the human counterpart is CYP2A6) and the murine P450T 15 α OH is the product of the Cyp2a-4 gene
Correspondence to: M. Pasanen at the above address