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      Lack of UGT1 isoforms in Gunn rats changes metabolic ratio and facilitates excretion of the food-derived carcinogen 2-amino-1-methyl-6-phenylimidazo.

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          Abstract

          UDP-glucuronosyltransferases (UGTs) play an important role in detoxification of endo- and xenobiotics. Deficiencies of these enzymes can have serious consequences, for example, in Crigler-Najjar disease Type I. Recently it was shown that the activated form of the abundant food-derived carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is glucuronidated mainly by UGT1 isoforms. Therefore UGT1 deficiency may have an important impact on metabolism and excretion of PhIP in the body and consequently for the susceptibility toward carcinogenic effects through PhIP. To test this hypothesis we investigated fate and distribution of PhIP in the UGT1-deficient Gunn rat. In 2 h after intravenous injection of PhIP, Gunn rats excreted significantly more PhIP and metabolites than control animals, which were age- and weight-matched Wistar rats. In bile, both glucuronides of N-OH-PhIP were reduced but, in urine, only the N3-glucuronide was reduced while the N2-glucuronide was elevated. The metabolic pathway ratio between 4'-hydroxylation 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 ratio in total), mostly because of the doubled amount of 4'-PhIP-sulfate in Gunn 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 sulfotransferases, which adds another clue to the potential importance of sulfotransferases in detoxification of PhIP.

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          Author and article information

          Journal
          Toxicol. Appl. Pharmacol.
          Toxicology and applied pharmacology
          Elsevier BV
          0041-008X
          0041-008X
          Jan 15 2001
          : 170
          : 2
          Affiliations
          [1 ] Laboratory of Experimental Hepatology, Department of Gastroenterology, Academic Medical Center, F0-116, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
          Article
          S0041008X00990902
          10.1006/taap.2000.9090
          11162778
          0c2f4bb1-a2a2-4000-84b1-2c66c959114c
          History

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