Induction of drug-metabolizing enzymes in gunn rat liver: Effect of polycyclic aromatic hydrocarbons on cytochrome P-450 regulation

Abstract

Response of congenitally jaundiced rats (Gunn rats) to administration of polycyclic aromatic hydrocarbons (PAH) was investigated and compared to that of Wistar rats. Unlike Wistar, Gunn males did not exhibit changes in the overall cytochrome P-450 content of hepatic microsomes. The first step in the induction process (i.e. presence of cytosolic receptors for PAH) was found present and functionally similar (number of sites, K d) to that of Wistar rats from which the Gunn strain is derived. An increase in monooxygenase activities related to P-450c and P-450d isoenzymes specifically induced by PAH was noticed, whereas no effect could be detected on the glucuronidation rate of either 4-nitrophenol, testosterone or estrone. As determined by immunoquantification after Western blotting, the iso-enzymatic profile of P-450 from PAH-treated male Gunn rats showed an increase of P-450c and P-450d accompanied by an equivalent decrease in P-4502c (major male-specific isoenzyme). The balance between increase in P-450c and P-450d and decrease in P-4502c may explain the absence of increase in the total P-450 in PAH-treated male Gunn rats. Such a response was not observed in PAH-treated male Wistar rats or in female rats of both strains. In contrast, the response of male Gunn rats to PB treatment was similar to that observed in Wistar rats, i.e. increase in overall cytochrome P-450 content of hepatic microsomes and of specific isoenzyme P-450 b/e. A possible regulation of P-450 isoenzyme synthesis by the intracellular haem pool might be involved.