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 Stillwell, W. G. Articles by Sinha, R. Search for Related Content PubMed PubMed Citation Articles by Stillwell, W. G. Articles by Sinha, R.

Urinary Excretion of Unmetabolized and Phase II Conjugates of 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline in Humans: Relationship to Cytochrome P4501A2 and N-Acetyltransferase Activity¹

Division of Toxicology [W. G. S., L. R. K., J. S. W., S. R. T.] and Department of Chemistry [S. R. T.], Massachusetts Institute of Technology, Cambridge, Massachusetts 02139-4307, and Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, Maryland 20892 [R. S.]

Cooking meat, fish, or poultry at high temperature gives rise to heterocyclic aromatic amines (HAAs), which may be metabolically activated to mutagenic or carcinogenic intermediates. The enzymes cytochrome P4501A2 (CYP1A2) and N-acetyltransferase (NAT2) are principally implicated in such biotransformations. We have determined the relationship between the activity of these two enzymes and the urinary excretion of unmetabolized and Phase II conjugates of the two HAAs MeIQx (2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline) and PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) in individuals fed a uniform diet containing high-temperature cooked meat. The subjects in the study ate meat containing known amounts of MeIQx and PhIP, and urine collections were made 0–12 and 12–24 h after a meal. MeIQx and PhIP were measured in urine after acid treatment that quantitatively hydrolyzes the Phase II conjugates to the respective parent amine. The extracts containing the HAAs were purified by immunoaffinity chromatography and analyzed by liquid chromatography using electrospray ionization-tandem mass spectrometry. The MeIQx content in the 0–12 h urine increased after acid hydrolysis by a factor of 3–21-fold. After acid treatment, the total amount of MeIQx (unmetabolized plus the N²-glucuronide and sulfamate metabolites) excreted in the 0–12 h urine was 10.5 ± 3.5% (mean ± SD) of the dose, whereas the total amount of PhIP [unmetabolized plus acid-labile conjugate(s)] in the 0–12 h period was 4.3 ± 1.7% (mean ± SD) of the dose. The total amount of PhIP in the 12–24 h urine after acid treatment was 0.9 ± 0.4% (mean ± SD) of the dose. Linear regression analysis of the amounts of MeIQx and PhIP excreted in the 0–12 h period expressed as a percentage of the ingested dose, for all subjects, gave a low but significant correlation (r = 0.37, P = 0.005). Linear regression analyses showed that lower total MeIQx (unmetabolized plus the N²-glucuronide and sulfamate metabolites) in urine was associated with higher CYP1A2 activity, whereas total PhIP (unmetabolized plus conjugated) in urine showed no association to CYP1A2 activity. These results indicate that in humans, MeIQx metabolism and disposition are more strongly influenced by CYP1A2 activity than are those of PhIP. Linear regression analysis found no association between NAT2 activity and the levels (unmetabolized plus acid-labile conjugates) of MeIQx or PhIP excreted in urine.

¹ This work was supported (Massachusetts Institute of Technology) by National Institute of Environmental Health Sciences Grant ES05622. The Finnigan TSQ 7000 was funded by United States Department of Energy Grant DE-FG02-95TE00056.

² To whom requests for reprints should be addressed, at the Division of Toxicology, Massachusetts Institute of Technology, Room 56-731A, 77 Massachusetts Avenue, Cambridge, MA 02139-4307.

Received 2/25/97. Accepted 6/18/97.

This article has been cited by other articles:

				R. J. Turesky, J.-M. Yuan, R. Wang, S. Peterson, and M. C. Yu Tobacco Smoking and Urinary Levels of 2-Amino-9H-Pyrido[2,3-b]Indole in Men of Shanghai, China Cancer Epidemiol. Biomarkers Prev., August 1, 2007; 16(8): 1554 - 1560. [Abstract] [Full Text] [PDF]

				M. A. Malfatti, K. H. Dingley, S. Nowell-Kadlubar, E. A. Ubick, N. Mulakken, D. Nelson, N. P. Lang, J. S. Felton, and K. W. Turteltaub The Urinary Metabolite Profile of the Dietary Carcinogen 2-Amino-1-Methyl-6-Phenylimidazo[4,5-b]Pyridine Is Predictive of Colon DNA Adducts after a Low-Dose Exposure in Humans Cancer Res., November 1, 2006; 66(21): 10541 - 10547. [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]

				W.G. Stillwell, R. Sinha, and S.R. Tannenbaum Excretion of the N2-glucuronide conjugate of 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine in urine and its relationship to CYP1A2 and NAT2 activity levels in humans Carcinogenesis, May 1, 2002; 23(5): 831 - 838. [Abstract] [Full Text] [PDF]

				K. S. Kulp, M. G. Knize, M. A. Malfatti, C. P. Salmon, and J. S. Felton Identification of urine metabolites of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine following consumption of a single cooked chicken meal in humans Carcinogenesis, November 1, 2000; 21(11): 2065 - 2072. [Abstract] [Full Text] [PDF]

				T.-M. Hong, P.-C. Yang, K. Peck, J. J. W. Chen, S.-C. Yang, Y.-C. Chen, and C.-W. Wu Profiling the Downstream Genes of Tumor Suppressor PTEN in Lung Cancer Cells by Complementary DNA Microarray Am. J. Respir. Cell Mol. Biol., September 1, 2000; 23(3): 355 - 363. [Abstract] [Full Text]

				U.K. Walle and T. Walle Transport of the cooked-food mutagen 2-amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine (PhIP) across the human intestinal Caco-2 cell monolayer: role of efflux pumps Carcinogenesis, November 1, 1999; 20(11): 2153 - 2157. [Abstract] [Full Text] [PDF]

				W. G. Stillwell, R. J. Turesky, R. Sinha, and S. R. Tannenbaum N-Oxidative Metabolism of 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) in Humans Excretion of the N2-Glucuronide Conjugate of 2-Hydroxyamino-MeIQx in Urine Cancer Res., October 1, 1999; 59(20): 5154 - 5159. [Abstract] [Full Text] [PDF]

				C. Y. Wang, M. Debiec-Rychter, H. A.J. Schut, P. Morse, R. F. Jones, C. Archer, C. M. King, and G. P. Haas N-Acetyltransferase expression and DNA binding of N-hydroxyheterocyclic amines in human prostate epithelium Carcinogenesis, August 1, 1999; 20(8): 1591 - 1596. [Abstract] [Full Text] [PDF]

				L. C. R. Kidd, W. G. Stillwell, M. C. Yu, J. S. Wishnok, P. L. Skipper, R. K. Ross, B. E. Henderson, and S. R. Tannenbaum Urinary Excretion of 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in White, African-American, and Asian-American Men in Los Angeles County Cancer Epidemiol. Biomarkers Prev., May 1, 1999; 8(5): 439 - 445. [Abstract] [Full Text]

				M. A. Malfatti, K. S. Kulp, M. G. Knize, C. Davis, J. P. Massengill, S. Williams, S. Nowell, S. MacLeod, K. H. Dingley, K. W. Turteltaub, et al. The identification of [2-14C]2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine metabolites in humans Carcinogenesis, April 1, 1999; 20(4): 705 - 713. [Abstract] [Full Text] [PDF]

				H. A.J. Schut and E. G. Snyderwine DNA adducts of heterocyclic amine food mutagens: implications for mutagenesis and carcinogenesis Carcinogenesis, March 1, 1999; 20(3): 353 - 368. [Abstract] [Full Text] [PDF]