UP-REGULATION OF CYP2A5 EXPRESSION BY PORPHYRINOGENIC AGENTS IN MOUSE-LIVER

Coumarin 7-hydroxylase (COH) activity is catalyzed by the Cyp2a-5 gene product (CYP2A5 enzyme) in mice. Mouse hepatic CYP2A5 expression is o ften increased in conditions in which other P450 forms are repressed, e.g. after the administration of heavy metals and other toxic agents k nown to affect cellular heme balance. In this study, the effect of var ious porphyrinogenic chemicals on the expression CYP2A5 and the key en zymes in heme metabolism was studied. Administration of single doses o f griseofulvin (1000 mg/kg), thioacetamide (10mg/kg) and aminotriazole (1000 mg/kg) to DBA/2 and C57BL/6 mice produced up to 10-fold increas es in hepatic COH catalytic activity. Dramatic, up to 130-fold increas es in response to the inducers was observed in the amount of CYP2A5 st eady-state mRNA. The mRNA contents of aminolevulinate synthase, ferroc helatase and heme oxygenase were also increased to a variable extent, possibly reflecting feed-back regulatory mechanisms. In D2 mice the CY P2A5 inducing effect of aminotriazole and thioacetamide, but not that of griseofulvin, pyrazole and phenobarbital, was abolished by exogenou sly administered heme arginate. In the B6 strain heme arginate treatme nt increased CYP2A5 expression but it did not affect the induction cau sed by porphyrinogenic agents. These results show that porphyrinogenic agents act as efficient inducers of CYP2A5, and suggest that regulati on of the transcription of the Cyp2a-5 gene could in some instances in volve heme-sensitive factors.