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