Carcinogenesis, Vol. 22, No. 7, 1087-1093,
July 2001
© 2001 Oxford University Press
CANCER BIOLOGY |
N-Glucuronidation of 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) and N-hydroxy-PhIP by specific human UDP-glucuronosyltransferases
Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory, PO Box 808, L-452, Livermore, CA 94551, USA
Glucuronidation is a major metabolic pathway in the biotransformation of many xenobiotics. Recent studies have shown that in humans, UDP-glucuronosyltransferase (UGT)-mediated glucuronidation plays a critical role in the detoxification of food-borne carcinogenic heterocyclic amines. 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), the most abundant carcinogenic heterocyclic amine found in well-cooked meats, has been shown to be extensively glucuronidated in humans. To determine which UGT isozymes are involved in the biotransformation of PhIP and the cytochrome P4501A2-mediated reactive intermediate N-hydroxy-PhIP, microsomes expressing human UGT1A1, -1A4, -1A6 or -1A9 were incubated with PhIP and N-hydroxy-PhIP and the reaction products analyzed by HPLC and ESI-MS. Incubations containing N-hydroxy-PhIP and UGT1A1 expressing microsomes, with an apparent Km of 4.58 µM and a Vmax of 4.18 pmol/min/mg protein, had the highest capacity to convert N-hydroxy-PhIP to N-hydroxy-PhIP-N2-glucuronide. Microsomes expressing UGT1A9 produced N-hydroxy-PhIP-N3-glucuronide at the highest rate with an apparent Km and Vmax of 3.73 µM and 4.07 pmol/min/mg, respectively. A third previously undefined glucuronide accounted for 31% of the total glucuronides formed from the UGT1A4 expressing microsomes. No glucuronide conjugates were detected from microsomes expressing UGT1A6. Incubations containing PhIP as substrate formed direct PhIP-glucuronides in microsomes expressing UGT1A1, UGT1A4 and UGT1A9 but at levels averaging 53-fold lower than when N-hydroxy-PhIP was used as the substrate. Knowing the glucuronidation capacity of the specific UGT isozymes involved in PhIP and N-hydroxy-PhIP glucuronidation should help in determining the individual susceptibility to the potential cancer risk from exposure to PhIP.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  R. W. Dellinger, G. Chen, A. S. Blevins-Primeau, J. Krzeminski, S. Amin, and P. Lazarus Glucuronidation of PhIP and N-OH-PhIP by UDP-glucuronosyltransferase 1A10 Carcinogenesis, November 1, 2007; 28(11): 2412 - 2418. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Malfatti, E. A. Ubick, and J. S. Felton The impact of glucuronidation on the bioactivation and DNA adduction of the cooked-food carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in vivo Carcinogenesis, November 1, 2005; 26(11): 2019 - 2028. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. K. Froehlich, U. Girreser, and B. Clement METABOLISM OF N-HYDROXYGUANIDINES (N-HYDROXYDEBRISOQUINE) IN HUMAN AND PORCINE HEPATOCYTES: REDUCTION AND FORMATION OF GLUCURONIDES Drug Metab. Dispos., October 1, 2005; 33(10): 1532 - 1537. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. M. Butler, Y. Duguay, R. C. Millikan, R. Sinha, J.-F. Gagne, R. S. Sandler, and C. Guillemette Joint Effects between UDP-Glucuronosyltransferase 1A7 Genotype and Dietary Carcinogen Exposure on Risk of Colon Cancer Cancer Epidemiol. Biomarkers Prev., July 1, 2005; 14(7): 1626 - 1632. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. L. Pool-Zobel, V. Selvaraju, J. Sauer, T. Kautenburger, J. Kiefer, K. K. Richter, M. Soom, and S. Wolfl Butyrate may enhance toxicological defence in primary, adenoma and tumor human colon cells by favourably modulating expression of glutathione S-transferases genes, an approach in nutrigenomics Carcinogenesis, June 1, 2005; 26(6): 1064 - 1076. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Peterson, J. Bigler, N. K. Horner, J. D. Potter, and J. W. Lampe Cruciferae Interact with the UGT1A1*28 Polymorphism to Determine Serum Bilirubin Levels in Humans J. Nutr., May 1, 2005; 135(5): 1051 - 1055. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. G. Walters, P. J. Young, C. Agus, M. G. Knize, A. R. Boobis, N. J. Gooderham, and B. G. Lake Cruciferous vegetable consumption alters the metabolism of the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in humans Carcinogenesis, September 1, 2004; 25(9): 1659 - 1669. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Svehlikova, S. Wang, J. Jakubikova, G. Williamson, R. Mithen, and Y. Bao Interactions between sulforaphane and apigenin in the induction of UGT1A1 and GSTA1 in CaCo-2 cells Carcinogenesis, September 1, 2004; 25(9): 1629 - 1637. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Fretland, U. S. Devanaboyina, M. A. Doll, S. Zhao, G. H. Xiao, and D. W. Hein Metabolic Activation of 2-Hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine in Syrian Hamsters Congenic at the N-Acetyltransferase 2 (NAT2) Locus Toxicol. Sci., August 1, 2003; 74(2): 253 - 259. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Xie, M.-F. Yeuh, A. Radominska-Pandya, S. P. S. Saini, Y. Negishi, B. S. Bottroff, G. Y. Cabrera, R. H. Tukey, and R. M. Evans Control of steroid, heme, and carcinogen metabolism by nuclear pregnane X receptor and constitutive androstane receptor PNAS, April 1, 2003; 100(7): 4150 - 4155. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Williams, B. J. Ring, V. E. Cantrell, K. Campanale, D. R. Jones, S. D. Hall, and S. A. Wrighton Differential Modulation of UDP-Glucuronosyltransferase 1A1 (UGT1A1)-Catalyzed Estradiol-3-glucuronidation by the Addition of UGT1A1 Substrates and Other Compounds to Human Liver Microsomes Drug Metab. Dispos., November 1, 2002; 30(11): 1266 - 1273. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Sachse, G. Smith, M. J.V. Wilkie, J. H. Barrett, R. Waxman, F. Sullivan, D. Forman, D. T. Bishop, and C.R. Wolf A pharmacogenetic study to investigate the role of dietary carcinogens in the etiology of colorectal cancer Carcinogenesis, November 1, 2002; 23(11): 1839 - 1850. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. K. Walle and T. Walle Induction of Human UDP-Glucuronosyltransferase UGT1A1 by Flavonoids---Structural Requirements Drug Metab. Dispos., May 1, 2002; 30(5): 564 - 569. [Abstract] [Full Text] [PDF]
|
|