Carcinogenesis Advance Access published online on July 17, 2007
Carcinogenesis, doi:10.1093/carcin/bgm164
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Glucuronidation of PhIP and N-OH-PhIP by UDP-glucuronosyltransferase 1A10
Cancer Prevention and Control (R.W.D., G.C., A.S.B-P., S.A., P.L.) and Chemical Carcinogenesis and Chemoprevention (J.K., S.A.) Programs, Penn State Cancer Institute; Departments of Pharmacology (R.W.D., A.S.B-P., J.K., S.A., P.L.) and Public Health Sciences (G.C., P.L.), Penn State University College of Medicine, Hershey, PA 17033
Corresponding author: Philip Lazarus, Ph.D., Penn State Cancer Institute, Penn State University College of Medicine, Rm. C3739D, MC-H069, 500 University Drive, Hershey, PA 17033; Fax: (717) 531-0480; Email: plazarus{at}psu.edu
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 (PAHs), are known to be detoxified by the UGT family of enzymes. Recently, our laboratory demonstrated that UGT1A10 has considerably more activity against PAHs 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 (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 overexpressing individual UGTs. Kinetic analysis revealed a 9- and 22-fold higher level of activity for UGT1A10 homogenates as compared to the next most active UGT, UGT1A1, against N-OH-PhIP as determined by Vmax/KM at the N3 and N2 positions, respectively. The polymorphic UGT1A10139Lys variant exhibited a 2- to 16-fold decrease in glucuronidation activity against PhIP and N-OH-PhIP, as compared to the wild-type UGT1A10139Glu 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.
Received March 7, 2007; revised June 29, 2007; accepted July 6, 2007.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. Tojcic, M.-O. Benoit-Biancamano, M. H. Court, R. J. Straka, P. Caron, and C. Guillemette In Vitro Glucuronidation of Fenofibric Acid by Human UDP-Glucuronosyltransferases and Liver Microsomes Drug Metab. Dispos., November 1, 2009; 37(11): 2236 - 2243. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. C. Olson, R. W. Dellinger, Q. Zhong, D. Sun, S. Amin, T. E. Spratt, and P. Lazarus Functional Characterization of Low-Prevalence Missense Polymorphisms in the UDP-Glucuronosyltransferase 1A9 Gene Drug Metab. Dispos., October 1, 2009; 37(10): 1999 - 2007. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Balliet, G. Chen, C. J. Gallagher, R. W. Dellinger, D. Sun, and P. Lazarus Characterization of UGTs Active against SAHA and Association between SAHA Glucuronidation Activity Phenotype with UGT Genotype Cancer Res., April 1, 2009; 69(7): 2981 - 2989. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Fujiwara, M. Nakajima, H. Yamanaka, and T. Yokoi Key Amino Acid Residues Responsible for the Differences in Substrate Specificity of Human UDP-Glucuronosyltransferase (UGT)1A9 and UGT1A8 Drug Metab. Dispos., January 1, 2009; 37(1): 41 - 46. [Abstract] [Full Text] [PDF]
|
|