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. 1980 Mar;77(3):1427–1431. doi: 10.1073/pnas.77.3.1427

There is a correlation between the DNA affinity and mutagenicity of several 3-amino-1-methyl-5H-pyrido[4,3-b]indoles.

J M Pezzuto, P P Lau, Y Luh, P D Moore, G N Wogan, S M Hecht
PMCID: PMC348508  PMID: 6990411

Abstract

3-Amino-1-methyl-5H-pyrido[4,3-b]indole, previously reported to be a component of tryptophan pyrolysates, is an intensely mutagenic compound requiring microsomal activation for expression of mutagenicity. We have found that this species and several synthetic analogs interact noncovalently with calf thymus DNA, as judged by both fluorescence quenching and differential dialysis. Remarkably, this noncovalent interaction correlated with the mutagenic potential of the compounds in a bacterial mutagenesis assay. Therefore, it is suggested that the mechanism of mutagenesis involves metabolic activation followed by physicochemical interaction with DNA; for these compounds, the latter step may be limiting for the expression of mutagenicity.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Albert A. Relations between molecular structure 6501 and biological activity: stages in the evolution of current concepts. Annu Rev Pharmacol. 1971;11:13–36. doi: 10.1146/annurev.pa.11.040171.000305. [DOI] [PubMed] [Google Scholar]
  2. Ames B. N., Durston W. E., Yamasaki E., Lee F. D. Carcinogens are mutagens: a simple test system combining liver homogenates for activation and bacteria for detection. Proc Natl Acad Sci U S A. 1973 Aug;70(8):2281–2285. doi: 10.1073/pnas.70.8.2281. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Ames B. N., Gurney E. G., Miller J. A., Bartsch H. Carcinogens as frameshift mutagens: metabolites and derivatives of 2-acetylaminofluorene and other aromatic amine carcinogens. Proc Natl Acad Sci U S A. 1972 Nov;69(11):3128–3132. doi: 10.1073/pnas.69.11.3128. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Ames B. N., Sims P., Grover P. L. Epoxides of carcinogenic polycyclic hydrocarbons are frameshift mutagens. Science. 1972 Apr 7;176(4030):47–49. doi: 10.1126/science.176.4030.47. [DOI] [PubMed] [Google Scholar]
  5. BROOKES P., LAWLEY P. D. EVIDENCE FOR THE BINDING OF POLYNUCLEAR AROMATIC HYDROCARBONS TO THE NUCLEIC ACIDS OF MOUSE SKIN: RELATION BETWEEN CARCINOGENIC POWER OF HYDROCARBONS AND THEIR BINDING TO DEOXYRIBONUCLEIC ACID. Nature. 1964 May 23;202:781–784. doi: 10.1038/202781a0. [DOI] [PubMed] [Google Scholar]
  6. Bresnick E., Vaught J. B., Chuang A. H., Stoming T. A., Bockman D., Mukhtar H. Nuclear aryl hydrocarbon hydroxylase and interaction of polycyclic hydrocarbons with nuclear components. Arch Biochem Biophys. 1977 May;181(1):257–269. doi: 10.1016/0003-9861(77)90504-5. [DOI] [PubMed] [Google Scholar]
  7. Colburn N. H., Boutwell R. K. The binding of beta-propiolactone and some related alkylating agents to DNA, RNA, and protein of mouse skin; relation between tumor-initiating power of alkylating agents and their binding to DNA. Cancer Res. 1968 Apr;28(4):653–660. [PubMed] [Google Scholar]
  8. Duportail G., Lami H. Studies of the interaction of the fluorophores harmine and harmaline with calf thymus DNA. Biochim Biophys Acta. 1975 Aug 6;402(1):20–30. doi: 10.1016/0005-2787(75)90365-2. [DOI] [PubMed] [Google Scholar]
  9. Edwards G. S., Wogan G. N., Sporn M. B., Pong R. S. Structure-activity relationships in DNA binding and nuclear effects of aflatoxin and anlogs. Cancer Res. 1971 Dec;31(12):1943–1950. [PubMed] [Google Scholar]
  10. Essigmann J. M., Croy R. G., Nadzan A. M., Busby W. F., Jr, Reinhold V. N., Büchi G., Wogan G. N. Structural identification of the major DNA adduct formed by aflatoxin B1 in vitro. Proc Natl Acad Sci U S A. 1977 May;74(5):1870–1874. doi: 10.1073/pnas.74.5.1870. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Fujino T., Fujiki H., Nagao M., Yahagi T., Seino Y., Sugimura T. The effect of norharman on the metabolism of benzo[alpha]pyrene by rat-liver microsomes in vitro in relation to its enhancement of the mutagenicity of benzo[alpha]pyrene. Mutat Res. 1978 Nov;58(2-3):151–158. doi: 10.1016/0165-1218(78)90004-6. [DOI] [PubMed] [Google Scholar]
  12. Gabbay E. J., Scofield R. E., Baxter C. S. Steric effects on the intercalation of aromatic cations to deoxyribonucleic acid. J Am Chem Soc. 1973 Nov 14;95(23):7850–7857. doi: 10.1021/ja00804a047. [DOI] [PubMed] [Google Scholar]
  13. Goshman L. M., Heidelberger C. Binding of tritium-labeled polycyclic hydrocarbons to DNA of mouse skin. Cancer Res. 1967 Sep;27(9):1678–1688. [PubMed] [Google Scholar]
  14. Harvey R. G., Dunne F. B. Multiple regions of metabolic activation of carcinogenic hydrocarbons. Nature. 1978 Jun 15;273(5663):566–568. doi: 10.1038/273566a0. [DOI] [PubMed] [Google Scholar]
  15. Hashimoto Y., Takeda K., Shudo K., Okamoto T., Sugimura T., Kosuge T. Rat liver microsome-mediated binding to DNA of 3-amino-1-methyl-5H-pyrido[4,3-b]indole, a potent mutagen isolated from tryptophan pyrolysate. Chem Biol Interact. 1978 Oct;23(1):137–140. doi: 10.1016/0009-2797(78)90047-9. [DOI] [PubMed] [Google Scholar]
  16. Hayashi K., Nagao M., Sugimura T. Interactions of norharman and harman with DNA. Nucleic Acids Res. 1977 Nov;4(11):3679–3685. doi: 10.1093/nar/4.11.3679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Heidelberger C. Chemical carcinogenesis. Annu Rev Biochem. 1975;44:79–121. doi: 10.1146/annurev.bi.44.070175.000455. [DOI] [PubMed] [Google Scholar]
  18. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  19. Lefèvre J. F., Fuchs R. P., Daune M. P. Comparative studies on the 7-iodo and 7-fluoro derivatives of N-acetoxy-N-2-acetylaminofluorene: binding sites on DNA and conformational change of modified deoxytrinucleotides. Biochemistry. 1978 Jun 27;17(13):2561–2567. doi: 10.1021/bi00606a016. [DOI] [PubMed] [Google Scholar]
  20. Levitt R. C., Legraverend C., Nebert D. W., Pelkonen O. Effects of harman and norharman on the mutagenicity and binding to DNA of benzo[a]pyrene metabolites in vitro and on aryl hydrocarbon hydroxylase induction in cell culture. Biochem Biophys Res Commun. 1977 Dec 21;79(4):1167–1175. doi: 10.1016/0006-291x(77)91129-9. [DOI] [PubMed] [Google Scholar]
  21. Lu A. Y., Levin W. The resolution and reconstitution of the liver microsomal hydroxylation system. Biochim Biophys Acta. 1974 Sep 16;344(2):205–240. doi: 10.1016/0304-4157(74)90004-5. [DOI] [PubMed] [Google Scholar]
  22. Miller J. A. Carcinogenesis by chemicals: an overview--G. H. A. Clowes memorial lecture. Cancer Res. 1970 Mar;30(3):559–576. [PubMed] [Google Scholar]
  23. Newberne P. M., Wogan G. N. Sequential morphologic changes in aflatoxin B carcinogenesis in the rat. Cancer Res. 1968 Apr;28(4):770–781. [PubMed] [Google Scholar]
  24. OMURA T., SATO R. THE CARBON MONOXIDE-BINDING PIGMENT OF LIVER MICROSOMES. I. EVIDENCE FOR ITS HEMOPROTEIN NATURE. J Biol Chem. 1964 Jul;239:2370–2378. [PubMed] [Google Scholar]
  25. Pezzuto J. M., Lea M. A., Yang C. S. Binding of metabolically activated benzo(a)pyrene to nuclear macromolecules. Cancer Res. 1976 Oct;36(10):3647–3653. [PubMed] [Google Scholar]
  26. Sims P., Grover P. L. Epoxides in polycyclic aromatic hydrocarbon metabolism and carcinogenesis. Adv Cancer Res. 1974;20:165–274. doi: 10.1016/s0065-230x(08)60111-6. [DOI] [PubMed] [Google Scholar]
  27. Skopek T. R., Liber H. L., Kaden D. A., Thilly W. G. Relative sensitivities of forward and reverse mutation assays in Salmonella typhimurium. Proc Natl Acad Sci U S A. 1978 Sep;75(9):4465–4469. doi: 10.1073/pnas.75.9.4465. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Skopek T. R., Liber H. L., Krolewski J. J., Thilly W. G. Quantitative forward mutation assay in Salmonella typhimurium using 8-azaguanine resistance as a genetic marker. Proc Natl Acad Sci U S A. 1978 Jan;75(1):410–414. doi: 10.1073/pnas.75.1.410. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Takeda K., Ohta T., Shudo K., Okamoto T., Tsuji K. Synthesis of a mutagenic principle isolated from tryptophan pyrolysate. Chem Pharm Bull (Tokyo) 1977 Aug;25(8):2145–2146. doi: 10.1248/cpb.25.2145. [DOI] [PubMed] [Google Scholar]

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