This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kadlubar, F. F. Articles by Miller, E. C. Search for Related Content PubMed PubMed Citation Articles by Kadlubar, F. F. Articles by Miller, E. C.

Hepatic Microsomal N-Glucuronidation and Nucleic Acid Binding of N-Hydroxy Arylamines in Relation to Urinary Bladder Carcinogenesis¹

McArdle Laboratory for Cancer Research, University of Wisconsin Medical Center, Madison, Wisconsin 53706

Uridine 5'-diphosphoglucuronic acid-fortified hepatic microsomes from dogs, rats, or humans rapidly metabolized [³H]-N-hydroxy-2-naphthylamine (N-HO-2-NA) to a water-soluble product that yielded 98% of the parent N-hydroxy amine upon treatment with ß-glucuronidase. The metabolite was identified as N-(ß-1-glucosiduronyl)-N-hydroxy-2-naphthylamine from ultraviolet, infrared, and mass spectral analyses of the glucuronide and its nitrone derivative. Incubation of N-hydroxy-1-naphthylamine (N-HO-1-NA), N-hydroxy-4-aminobiphenyl (N-HO-ABP), or the N-hydroxy derivatives of 2-aminofluorene, 4-aminoazobenzene, or N-acetyl-2-aminofluorene with uridine 5'-diphosphoglucuronic acid-fortified hepatic microsomes also yielded water-soluble products. ß-Glucuronidase treatment released 80 to 90% of the [³H]-N-HO-1-NA and [³H]-N-HO-ABP conjugates as tritiated ether-extractable derivatives. N-HO-1-NA, N-HO-2-NA, and N-HO-ABP and the glucuronides of these N-hydroxy arylamines were relatively stable and nonreactive near neutral pH. At pH 5, the N-glucuronide of N-HO-2-NA and the presumed N-glucuronides of N-HO-1-NA and N-HO-ABP were rapidly hydrolyzed to the N-hydroxy arylamines that were then converted to reactive derivatives capable of binding covalently to nucleic acids.

These data support the concept that arylamine bladder carcinogens are N-oxidized and N-glucuronidated in the liver and that the N-glucuronides are transported to the urinary bladder. The hydrolysis of the glucuronides to N-hydroxy arylamines and the conversion of the latter derivatives to highly reactive electrophilic arylnitrenium ions in the normally acidic urine of dogs and humans may be critical reactions for tumor induction in the urinary bladder.

¹ This research was supported in part by funds from USPHS Grants CA-07175, CA-15785, and 5-T32-CA-09020.

² Postdoctoral Fellow of the Foundation for Cancer Research, Chicago, from September 1973 to September 1975. Present address: National Center for Toxicological Research, Jefferson, Ark. 72079.

³ To whom requests for reprints should be addressed.

Received 8/30/76. Accepted 12/ 6/76.

This article has been cited by other articles:

				G. Lower Jr, T Nilsson, C. Nelson, H Wolf, T. Gamsky, and G. Bryan N-acetyltransferase phenotype and risk in urinary bladder cancer: approaches in molecular epidemiology. Preliminary results in Sweden and Denmark Int. J. Epidemiol., March 11, 2007; (2007) dyl290v1. [Full Text] [PDF]

				N. Rothman, M. Garcia-Closas, and D. W Hein Commentary: Reflections on G. M. Lower and colleagues' 1979 study associating slow acetylator phenotype with urinary bladder cancer: meta-analysis, historical refinements of the hypothesis, and lessons learned Int. J. Epidemiol., February 1, 2007; 36(1): 23 - 28. [Full Text] [PDF]

				C. Chen, L. Meng, X. Ma, K. W. Krausz, Y. Pommier, J. R. Idle, and F. J. Gonzalez Urinary Metabolite Profiling Reveals CYP1A2-Mediated Metabolism of NSC686288 (Aminoflavone) J. Pharmacol. Exp. Ther., September 1, 2006; 318(3): 1330 - 1342. [Abstract] [Full Text] [PDF]

				Z. Yan, G. W. Caldwell, D. Gauthier, G. C. Leo, J. Mei, C. Y. Ho, W. J. Jones, J. A. Masucci, R. W. Tuman, R. A. Galemmo Jr., et al. N-GLUCURONIDATION OF THE PLATELET-DERIVED GROWTH FACTOR RECEPTOR TYROSINE KINASE INHIBITOR 6,7-(DIMETHOXY-2,4-DIHYDROINDENO[1,2-C]PYRAZOL-3-YL)-(3-FLUORO-PHENYL)-AMINE BY HUMAN UDP-GLUCURONOSYLTRANSFERASES Drug Metab. Dispos., May 1, 2006; 34(5): 748 - 755. [Abstract] [Full Text] [PDF]

				Z. Hu and P. G. Wells Human Interindividual Variation in Lymphocyte UDP-Glucuronosyltransferases as a Determinant of In Vitro Benzo[a]pyrene Covalent Binding and Cytotoxicity Toxicol. Sci., March 1, 2004; 78(1): 32 - 40. [Abstract] [Full Text] [PDF]

				L. Airoldi, F. Orsi, C. Magagnotti, R. Coda, D. Randone, G. Casetta, M. Peluso, A. Hautefeuille, C. Malaveille, and P. Vineis Determinants of 4-aminobiphenyl-DNA adducts in bladder cancer biopsies Carcinogenesis, May 1, 2002; 23(5): 861 - 866. [Abstract] [Full Text] [PDF]

				M. D. Boudreau, D. G. Baker, H. W. Taylor, S. A. Barker, and J. C. Means Suppression of Arylamine Toxicity in the Fischer-344 Rat Following Ingestion of a Complex Mixture Toxicol Pathol, April 1, 2001; 29(3): 333 - 343. [Abstract] [PDF]

				M. Ciotti, V. M. Lakshmi, N. Basu, B. B. Davis, I. S. Owens, and T. V. Zenser Glucuronidation of benzidine and its metabolites by cDNA-expressed human UDP-glucuronosyltransferases and pH stability of glucuronides Carcinogenesis, October 1, 1999; 20(10): 1963 - 1969. [Abstract] [Full Text] [PDF]

				T. V. Zenser, V. M. Lakshmi, and B. B. Davis Human and Escherichia coli beta -Glucuronidase Hydrolysis of Glucuronide Conjugates of Benzidine and 4-Aminobiphenyl, and their Hydroxy Metabolites Drug Metab. Dispos., September 1, 1999; 27(9): 1064 - 1067. [Abstract] [Full Text]

				C. D. Davis, Y. Feng, D. W. Hein, and J. W. Finley The Chemical Form of Selenium Influences 3,2'-Dimethyl-4-aminobiphenyl-DNA Adduct Formation in Rat Colon J. Nutr., January 1, 1999; 129(1): 63 - 69. [Abstract] [Full Text] [PDF]

				S.-H. L. Chiu and S.-E. W. Huskey Species Differences in N-Glucuronidation Drug Metab. Dispos., September 1, 1998; 26(9): 838 - 847. [Abstract] [Full Text]

				M. D. Green and T. R. Tephly Glucuronidation of Amine Substrates by Purified and Expressed UDP-Glucuronosyltransferase Proteins Drug Metab. Dispos., September 1, 1998; 26(9): 860 - 867. [Abstract] [Full Text]

				S. M. Cohen Urinary Bladder Carcinogenesis Toxicol Pathol, January 1, 1998; 26(1): 121 - 127. [Abstract] [PDF]

				J. H. Lin and A. Y. H. Lu Role of Pharmacokinetics and Metabolism in Drug Discovery and Development Pharmacol. Rev., December 1, 1997; 49(4): 403 - 449. [Abstract] [Full Text] [PDF]

				V. M. Lakshmi, T. V. Zenser, and B. B. Davis Rat Liver Cytochrome P450 Metabolism of N-Acetylbenzidine and N,N'-Diacetylbenzidine Drug Metab. Dispos., April 1, 1997; 25(4): 481 - 488. [Abstract] [Full Text]

				S. Cohen and L. Ellwein Cell proliferation in carcinogenesis Science, August 31, 1990; 249(4972): 1007 - 1011. [Abstract] [PDF]

				A. Weston, D. K. Manchester, A. Povey, and C. C. Harris Detection of Carcinogen-Macromolecular Adducts in Humans International Journal of Toxicology, September 1, 1989; 8(5): 913 - 932. [Abstract] [PDF]

				C. Hoch-Ligeti, C. C. Congdon, M. K. Deringer, J. D. Strandberg, and H. L. Stewart Hemangiopericytoma and Other Tumors of Urinary Tract of Guinea Pigs Toxicol Pathol, January 1, 1980; 8(1): 1 - 8. [Abstract] [PDF]

				N Kinoshita and H. Gelboin beta-Glucuronidase catalyzed hydrolysis of benzo(a)pyrene-3-glucuronide and binding to DNA Science, January 20, 1978; 199(4326): 307 - 309. [Abstract] [PDF]