Glucuronidation of the lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) by rat UDP-glucuronosyltransferase 2B1

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone and its major metabolite, 4- (methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), are potent lung carcino gens in animals. UDP-glucuronosyltransferase (UGT)-mediated glucuronidation of NNAL is a potentially important detoxification pathway for these carcin ogens. To identify the UGT isozyme(s) involved in this pathway, we examined the glucuronidation of NNAL in rat liver microsomes and homogenates from c ell lines overexpressing specific UGT isozymes. NNAL glucuronidation was in duced in liver microsomes from rats treated with family 2 UGT inducers incl uding phenobarbitol and 3,5-di-tert-butyl-4-hydroxytoluene, which exhibited 1.7- and 2.6-fold higher rates of glucuronidation than microsomes from con trol rats. The rates of NNAL glucuronidation in liver microsomes from GUNN (deficient in family 1 UGTs) and RHA parental control rats were similar. Al l rat liver microsomes used in the present study catalyzed the glucuronidat ion of (S)-NNAL at a rate between 3.5 and 5.5 times that of the glucuronida tion of (R)-NNAL. Liver microsomes from Wistar rats exhibiting the low-andr osterone glucuronidation phenotype characteristic of the UGT2B2-deficient g enotype glucuronidated NNAL at a rate similar to microsomes from Wistar rat s exhibiting the high-androsterone glucuronidation phenotype/UGT2B2 [+] gen otype. Homogenates from UGT2B1-overexpressing cells catalyzed the glucuroni dation of NNAL at a K-m of 745 mu M. As with rat liver microsomes, NNAL-GIu c I was the major diastereomer formed by UGT2B1. Glucuronidation of NNAL wa s not detected with homogenates from UGT2B12-overexpressing cells. These re sults suggest that UGT2B1 plays an important role in the glucuronidation of NNAL in the rat.