Drug metabolism in gunn rats: Inability to increase bilirubin glucuronidation by phenobarbital treatment

Abstract

The components of the microsomal mixed-function oxidase system in Wistar and Gunn rats were the same, as were the overall hydroxylation reactions ( p-nitroanisole O-demethylase, aryl hydrocarbon hydroxylase). The Gunn rat was, however, almost totally devoid of bilirubin glucuronidation activity. The UDP glucuronosyltransferase activity towards p-nitrophenol in the Gunn rat was in liver about 60 per cent and in the small intestinal mucosa about 10 per cent of that in the Wistar rat. The mono-oxygenation step in hepatic microsomal drug metabolism was induced in a similar way by phenobarbital treatment in both Wistar and Gunn strain rats, but no significant enhancement of the mono-oxygenase activity could be observed in the gut. The trypsin digestion of hepatic microsomes increased the specific UDPglucuronosyltransferase activity. Phenobarbital treatment enhanced the p-nitrophenol glucuronidation in livers of both Wistar (3-fold) and Gunn strain (2-fold) rats, but the bilirubin glucuronidation was enhanced (2-fold) only in Wistar rats. Phenobarbital-enhanced transferase activities could be detected only if the microsomes had been digested with trypsin before determination of the enzyme activity. The UDPglucuronosyltransferase activity in the small intestinal mucosa was not enhanced by phenobarbital. The results suggest that bilirubin and p-nitrophenol are conjugated by distinct enzymes and that the enzyme activities for mono-oxygenation and glucuronidation are controlled by different mechanisms. The microenvironment of the UDP glucuronosyltransferase is most probably similar in Gunn and Wistar rats.