Glucuronidation of PhIP and N-OH-PhIP by UDP-glucuronosyltransferase 1A10

摘要: The UDP-glucuronosyltransferase (UGT) 1A10 is an extra-hepatic enzyme that plays important role in the glucuronidation of a variety endogenous and exogenous substances expressed throughout aerodigestive digestive tracts. Two classes carcinogens target colon, heterocyclic amines (HCAs) polycyclic aromatic hydrocarbons, are known to be detoxified by UGT family enzymes. Recently, our laboratory demonstrated UGT1A10 has considerably more activity against hydrocarbons vitro than any other member. In this study, we focused on HCA, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), its bioactivated metabolite, N-hydroxy-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-OH-PhIP). We exhibited significantly higher rate PhIP N-OH-PhIP member using whole-cell homogenates HEK293 cells over-expressing individual UGTs. Kinetic analysis revealed 9- 22-fold level for as compared with next most active UGT, UGT1A1, determined maximum rate/apparent Michaelis constant (V(max)/K(M)) at N3 N2 positions, respectively. polymorphic UGT1A10(139Lys) variant 2- 16-fold decrease N-OH-PhIP, wild-type UGT1A10(139Glu) isoform. These data suggest may play susceptibility HCA-induced colon cancer.