Carcinogenesis, Vol. 20, No. 6, 1107-1114,
June 1999
© 1999 Oxford University Press
Carcinogenesis |
Glucuronidation of 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine by human microsomal UDP-glucuronosyltransferases: identification of specific UGT1A family isoforms involved
1 University of Arkansas for Medical Sciences, Surgical Oncology Department, 4301 West Markham Street, VA Research Slot 151 and
2 University of Arkansas for Medical Sciences, Department of Biochemistry, Little Rock, AR 72205,
3 Department of Pharmacology, The University of Iowa, Iowa City, IA 52242,
4 Department of Pharmacology, UCSD Cancer Center, University of California-San Diego, La Jolla, CA 92093,
5 John L.McClellan Memorial Veterans Administration Medical Center, Little Rock, AR 72205 and
6 National Center for Toxicological Research, Jefferson, AR 72079, USA
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine is a heterocyclic aromatic amine found in cooked meats and dietary exposure to PhIP has been implicated in the etiology of colon cancer in humans. PhIP, along with other heterocyclic aromatic amines, requires metabolic activation to exhibit genotoxic effects. PhIP is initially oxidized by the activity of cytochrome P4501A2 to produce 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-OH-PhIP), a reaction occurring primarily in the liver. Whereas subsequent biotransformation of N-OH-PhIP via acetylation or sulfation can produce reactive electrophiles that readily bind to DNA, N-glucuronidation, catalyzed by UDP-glucuronosyltransferases (UGTs), functions as a detoxification mechanism. Although hepatic glucuronidation of N-OH-PhIP has been well characterized, the extrahepatic metabolism of this compound is poorly understood. Studies in our laboratory now indicate that the intestinal tract, and particularly the colon, is a significant site of glucuronidation of N-OH-PhIP. When assays were performed with microsomes prepared from the mucosa of the intestinal tract, it was determined that glucuronidation of N-OH-PhIP occurs throughout the intestinal tract, with activity approximately three times higher in the colon as that found in the upper intestine. Glucuronidation rates from colon microsomes showed considerable interindividual variability and incubation with N-OH-PhIP yielded two glucuronides. HPLC analysis showed that the predominant product formed is the N-OH-PhIP-N2-glucuronide, while the N3-glucuronide accounts for <10% of the total glucuronidation product. These rates approach the rates found in human liver microsomes, demonstrating the significance of extrahepatic metabolism of this food-borne carcinogen. Subsequent assays with human recombinant UGTs demonstrated that at least four human UGT isoforms, all from the UGT1A subfamily, are capable of catalyzing the biotransformation of N-OH-PhIP. Members of the UGT2B family available for this study did not conjugate N-OH-PhIP, although immunoinhibition studies in human liver microsomes strongly suggest the involvement of a UGT2B isoform(s) in this organ.
Abbreviations: AIA, amino-imidazoazaarene; N-OH-PhIP, 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine; PhIP, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine; UDP-GlcUA, UDP-glucuronic acid; UGTs, UDP-glucuronosyltransferases.
7 To whom correspondence should be addressed Email: nowellsusana{at}exchange.uams.edu
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