Glucuronidation of PhIP and N-OH-PhIP by UDP-glucuronosyltransferase 1A10. Other Scholarly Work

Dellinger, Ryan W, Chen, Gang, Blevins-Primeau, Andrea S et al. (2007). Glucuronidation of PhIP and N-OH-PhIP by UDP-glucuronosyltransferase 1A10. . 28(11), 2412-2418. 10.1093/carcin/bgm164

cited authors

  • Dellinger, Ryan W; Chen, Gang; Blevins-Primeau, Andrea S; Krzeminski, Jacek; Amin, Shantu; Lazarus, Philip

fiu authors

abstract

  • 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.

publication date

  • November 1, 2007

keywords

  • Blotting, Western
  • Cell Line
  • Chromatography, High Pressure Liquid
  • Glucuronides
  • Glucuronosyltransferase
  • Humans
  • Imidazoles
  • Kinetics
  • Mass Spectrometry
  • Pyridines

Digital Object Identifier (DOI)

Medium

  • Print-Electronic

start page

  • 2412

end page

  • 2418

volume

  • 28

issue

  • 11