A comparison of uridine diphosphate-glucuronosyl-transferase and other drug metabolizing enzyme activities between two mutant strains of Wistar rats with a genetic deficiency in bilirubin or androsterone glucuronidation.

A jaundiced rat strain was derived from a cross between Gunn and Wistar-Imamichi rats, and inbreeding was continued by forced heterozygosis with jaundice locus. These Gunn rats have black pigment on heads and a black stripe on their backs similar to Long-Evans rats. Wistar rats with low activity in androsterone (AD) glucuronidation were selected and inbred (LA Wistar rats). The levels of hepatic uridine diphosphate-glucuronosyltransferase (GT) and sulfotransferase (ST) activities as well as cytochrome P-450 contents were compared in these mutant strains. Gunn rats were devoid of bilirubin (BL) GT activity but had high AD GT activity. LA Wistar rats had very low AD GT activity but showed high BL GT activity. Native and Triton X-100-stimulated GT activities toward 2-aminophenol and 4-nitrophenol (NP) were much lower in Gunn rats than in LA Wistar rats. When N-nitrosodiethylamine was added to the incubation media, these GT activities were stimulated equally to high levels in both mutants. N-Nitrodiethylamine provided a similar stimulatory effect on NP GT activity. There were no significant differences in ST activities toward cortisol, AD and NP and cytochrome P-450 contents in the two mutant strains. These results indicate that Gunn and LA Wistar rats have a different deficiency in GT isoenzymes.

The molecular basis of the inherited deficiency of androsterone UDP-glucuronyltransferase in Wistar rats.

A major UDP-glucuronyltransferase isoenzyme in rat liver (51 kDa), corresponding to androsterone glucuronidating activity, has been identified by immunoblot analysis. This isoenzyme is absent from Wistar rats exhibiting the low androsterone (LA) UDP-glucuronyltransferase activity exhibiting the low androsterone (LA) UDP-glucuronyltransferase activity phenotype. Northern blot analysis of total RNA from normal and androsterone glucuronidation deficient Wistar rats demonstrated that the mRNA encoding this protein was not synthesised. Differences in restriction fragment length observed on Southern blotting of genomic DNA from LA Wistar rats indicate that this inherited deficiency is the result of a deletion in the androsterone UDP-glucuronyltransferase gene.