Lack of UGT1 isoforms in Gunn rats changes metabolic ratio and facilitatesexcretion of the food-derived carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine

UDP-glucuronosyltransferases (UGTs) play an important role in detoxificatio n of endo- and xenobiotics. Deficiencies of these enzymes can have serious consequences, for example, in Crigler-Najjar disease Type I. Recently it wa s shown that the activated form of the abundant food-derived carcinogen 2-a mino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is glucuronidated mainl y by UGT1 isoforms. Therefore UGT1 deficiency may have an important impact on metabolism and excretion of PhIP in the body and consequently for the su sceptibility toward carcinogenic effects through PhIP. To test this hypothe sis we investigated fate and distribution of PhIP in the UGT1-deficient Gun n rat. In 2 h after intravenous injection of PhIP, Gunn rats excreted signi ficantly more PhIP and metabolites than control animals, which were age- an d weight-matched Wistar rats. In bile, both glucuronides of N-OH-PhIP were reduced but, in urine, only the N-3-glucuronide was reduced while the N-2-g lucuronide was elevated. The metabolic pathway ratio between 4'-hydroxylati on and N-hydroxylation was dramatically changed in the Gunn rat (five times higher in bile and doubled in urine, resulting in a four times higher rati o in total), mostly because of the doubled amount of 4'-PhIP-sulfate in Gun n rats compared to Wistar rats. Tissue levels of PhIP and metabolites were significantly lower in liver and colon of the Gunn rats. We conclude that, in Gunn rats, PhIP is alternatively metabolized through UGT2B enzymes and s ulfotransferases, which adds another clue to the potential importance of su lfotransferases in detoxification of PhIP. (C) 2001 Academic Press.