This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services 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 Endo, H. Articles by Snyderwine, E. G. Search for Related Content PubMed PubMed Citation Articles by Endo, H. Articles by Snyderwine, E. G.

Mutagenic Specificity of 2-Amino-3-methylimidazo[4,5-f]quinoline and 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in the supF Shuttle Vector System

Laboratory of Experimental Carcinogenesis, Division of Cancer Etiology, National Cancer Institute, Bethesda, Maryland 20892-0037 [H. E., E. G. S.], and Department of Pathology, Medical College of Ohio, Toledo, Ohio 43699-0008 [H. A. J. S.]

2-Amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are heterocyclic amine mutagens/carcinogens formed from the cooking of meat. Here we used the pSP189 shuttle vector developed by Parris and Seidman (Gene, 117: 1–5, 1992) to study and compare the mutation spectra induced by these compounds. pSP189 was adducted by reaction with the N-acetoxy derivatives of IQ or PhIP. ³²P-Postlabeling analysis was used to measure the C₈-guanine adduct level and the total adduct levels formed in the plasmid. Plasmids were replicated and mutagenized in repair-proficient [GM0637(SV40)] or repair-deficient [XP12Be(SV40)] human fibroblasts. Resulting inactivation mutations in the supF gene were determined by the formation of white or light blue colonies on indicator bacteria (carrying a lacZ amber mutation) and cycle sequencing. With both compounds in either cell line, 85–93% of the mutations induced were base substitutions and the remainder of the mutations were base deletions. The majority of the substitution mutations involved a single base, and nearly all base substitution mutations (>97%) were at guanine. This latter finding is consistent with the results from ³²P-postlabeling showing that both compounds adduct to the guanine base with the major adduct being formed at the C₈-guanine position. The predominant mutation found with IQ and PhIP in either cell line was G:C to T:A transversion, followed by G:C to A:T transition, and then G:C to C:G transversion; these mutations accounted for 59–72%, 19–27%, and 6–14% of total base substitution mutations, respectively. There was a preference seen with both compounds to induce mutations at a guanine base having a neighboring guanine or cytosine (i.e., GG and GC sites). However, despite the striking similarity in the kinds of base substitution mutations induced by IQ and PhIP, their mutation spectra were distinct. For example, in repair-proficient cells, 26% of the mutations induced with PhIP, but not with IQ, also involved a GA site, containing the 5-base pair sequence 5'-GCAGA-3'. Mutation spectra for IQ and PhIP were also different between repair-deficient and repair-proficient cells. The findings shown here may serve to be predictive of the kinds of mutations induced by the adducts of IQ and PhIP in oncogenes and tumor suppressor genes altered during heterocyclic amine-induced carcinogenesis.

¹ Recipient of a Japanese Overseas Cancer Fellowship from the Foundation for Promotion of Cancer Research.

² To whom requests for reprints should be addressed, at Laboratory of Experimental Carcinogenesis, National Cancer Institute, Building 37, Room 3C28, Bethesda, MD 20892.

Received 2/10/94. Accepted 5/16/94.

This article has been cited by other articles:

				E. G. Snyderwine, H.-S. Yoon, L. P. Knight-Jones, M. Tran, H. A.J. Schut, and M. Yu Mutagenesis and DNA adduct formation in the mouse mammary gland exposed to 2-hydroxyamino-1-methyl-6-phenylimidazo-[4,5-b]pyridine in whole organ culture Mutagenesis, January 1, 2003; 18(1): 7 - 12. [Abstract] [Full Text] [PDF]

				M. Yu, M. L. Jones, M. Gong, R. Sinha, H. A.J. Schut, and E. G. Snyderwine Mutagenicity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in the mammary gland of Big Blue rats on high-and low-fat diets Carcinogenesis, May 1, 2002; 23(5): 877 - 884. [Abstract] [Full Text] [PDF]

				T. Ubagai, M. Ochiai, T. Kawamori, H. Imai, T. Sugimura, M. Nagao, and H. Nakagama Efficient induction of rat large intestinal tumors with a new spectrum of mutations by intermittent administration of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in combination with a high fat diet Carcinogenesis, January 1, 2002; 23(1): 197 - 200. [Abstract] [Full Text] [PDF]

				J.C. Klein, R.B. Beems, P.E. Zwart, M. Hamzink, G. Zomer, H.v. Steeg, and C.F.v. Kreijl Intestinal toxicity and carcinogenic potential of the food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in DNA repair deficient XPA-/- mice Carcinogenesis, April 1, 2001; 22(4): 619 - 626. [Abstract] [Full Text] [PDF]

				J.A. Williams, F.L. Martin, G.H. Muir, A. Hewer, P.L. Grover, and D.H. Phillips Metabolic activation of carcinogens and expression of various cytochromes P450 in human prostate tissue Carcinogenesis, September 1, 2000; 21(9): 1683 - 1689. [Abstract] [Full Text] [PDF]

				J.A. Williams, E. M. Stone, B. C. Millar, A. Hewer, and D. H. Phillips Pathways of heterocyclic amine activation in the breast: DNA adducts of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) formed by peroxidases and in human mammary epithelial cells and fibroblasts Mutagenesis, March 1, 2000; 15(2): 149 - 154. [Abstract] [Full Text] [PDF]

				S. A.M. Bol, J. Horlbeck, J. Markovic, J. G. de Boer, R. J. Turesky, and A. Constable Mutational analysis of the liver, colon and kidney of Big Blue(R) rats treated with 2-amino-3-methylimidazo[4,5-f]quinoline Carcinogenesis, January 1, 2000; 21(1): 1 - 6. [Abstract] [Full Text] [PDF]

				G. Paladino, B. Weibel, and C. Sengstag Heterocyclic aromatic amines efficiently induce mitotic recombination in metabolically competent Saccharomyces cerevisiae strains Carcinogenesis, November 1, 1999; 20(11): 2143 - 2152. [Abstract] [Full Text] [PDF]

				E. Okochi, N. Watanabe, Y. Shimada, S. Takahashi, K. Wakazono, T. Shirai, T. Sugimura, M. Nagao, and T. Ushijima Preferential induction of guanine deletion at 5'-GGGA-3' in rat mammary glands by 2-amino- 1-methyl-6-phenylimidazo[4,5-b]pyridine Carcinogenesis, October 1, 1999; 20(10): 1933 - 1938. [Abstract] [Full Text] [PDF]

				D.-Y. Ryu, V. S. W. Pratt, C. D. Davis, H. A. J. Schut, and E. G. Snyderwine In Vivo Mutagenicity and Hepatocarcinogenicity of 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) in Bitransgenic c-myc/{{lambda}}lacZ Mice Cancer Res., June 1, 1999; 59(11): 2587 - 2592. [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]

				M. S. Solomon, P.-M. L. Morgenthaler, R. J. Turesky, and J. M. Essigmann Mutational and DNA Binding Specificity of the Carcinogen 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline J. Biol. Chem., August 2, 1996; 271(31): 18368 - 18374. [Abstract] [Full Text] [PDF]