Abstract
The molecular mechanisms by which aflatoxin B1 (AFB1) produces its biological effects are poorly understood. Many of the biochemical effects of the aflatoxins and other chemical carcinogens are mediated by activation through metabolism by one or more of the mixed-function oxidases and subsequent covalent modification of cellular macromolecules (1). Experimental evidence indicates that AFB1-2,3-oxide is the ultimate reactive metabolite (2,3). It is reasonable that the sites and amount of macromolecular damage play essential roles determining molecular alterations and consequently observable biological effects. The consequences of covalent damage once formed will depend upon the ability of a cell or tissue to repair (correctly or incorrectly) or circumvent damage to essential cellular components before they are lethal or result in permanent change in the molecular program of the cell. For example, cells from patients with xeroderma pigmentosum that are defective in excision repair have increased sensitivity to ultraviolet (UV) light and some chemical agents. Conversely, cells competent for repair that are given adequate time to remove lesions from DNA before critical events exhibit increased survival (4). Thus, the kinetics of formation of this macromolecular damage and its repair are important. We have studied the covalent products formed in DNA of species sensitive and resistant to the biological effects of AFB1 for correlations that may exist between the formation of these products, their removal, and biological responses to their presence.
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References
Miller, E.C. 1978. Some current perspectives on chemical carcinogenesis in humans and experimental animals: Presidential address. Cancer Res. 38: 1479–1496.
Swenson, D.H., E.C. Miller, and J.A. Miller. 1974. Aflatoxin B1–2,3-oxide: Evidence for its formation in rat liver in vivo and by human microsomes in vitro. Biochem. Biophys. Res. Comm. 60: 1036–1043.
Swenson, D.H., J. Lin, E.C. Miller, and J.A. Miller. 1977. Aflatoxin B1–2,3-oxide as a probable intermediate in the covalent binding of aflatoxins B1 and B2 to rat liver DNA and ribosomal RNA in vivo. Cancer Res. 37: 172–181.
Heflich, R.H., R.M. Hazard, L. Lommel, J.D. Scribner, V.M. Maher, and J.J. McCormick. 1980. A comparison of the DNA binding, cytotoxicity, and repair synthesis induced in human fibroblasts by reactive derivatives of aromatic amide carcinogens. Chem. Biol. Interact. 29: 43–56.
Wogan, G.N., and W.F. Busby. 1980. Naturally occurring carcinogens. In: Toxic Constituents of Plant Foodstuffs, second edition. I.E. Leiner, ed. Academic Press: New York. pp. 329–369.
Gurtoo, H.L., and R.P. Dahms. 1979. Effects of inducers and inhibitors on the metabolism of aflatoxin Bi by rat and mouse. Biochem. Pharmacol. 28: 3441–3449.
Schabort, J.C., and M. Steyn. 1969. Substrate and phenobarbital inducible aflatoxin 4-hydroxylation and aflatoxin metabolism by rat liver microsomes. Biochem. Pharmacol. 18: 2241–2252.
Croy, R.G., and G.N. Wogan. 1979. Identification of an aflatoxin P1-DNA adduct formed in vivo in rat liver. Proc. Am. Assoc. Cancer Res. 20: 182.
Garner, R.C., and C.M. Wright. 1975. Binding of [14C]Aflatoxin Bi to cellular macromolecules in the rat and hamster. Chem. Biol. Interact. 11: 123–131.
Gelboin, H.V., J.S. Wortham, R.G. Wilson, M. Friedman, and G.N. Wogan. 1966. Rapid and marked inhibition of rat liver RNA polymerase by aflatoxin B1. Science 154: 1205–1206.
Clifford, J.I., and K.R. Rees. 1966. Aflatoxin: a site of action in the rat liver cell. Nature 209: 312–313.
Edwards, G.S., and G.N. Wogan. 1970. Aflatoxin inhibition of template activity of rat liver chromatin. Biochim. Biophys. Acta 224: 597–607.
Yu, F. 1977. Mechanism of aflatoxin B1 inhibition of rat hepatic nuclear RNA synthesis. J. Biol. Chem. 252: 3245–3151.
Wong, J.J., and D.P. Hsieh. 1976. Mutagenicity of aflatoxins related to their metabolism and carcinogenic potential. Proc. Natl. Acad. Sci. USA 73: 2241–2244.
Krahn, D.F., and C. Heidelberger. 1977. Liver homogenate-mediated mutagenesis in Chinese hamster V79 cells by polycyclic aromatic hydrocarbons and aflatoxins. Mutat. Res. 46: 27–44.
Essigmann, J.M., R.G. Croy, A.M. Nadzan, W.F. Busby, V.N. Reinhold, G. Buchi, and G.N. Wogan. 1977. Structural identification of the major DNA adduct formed by aflatoxin B1 in vitro. Proc. Natl. Acad. Sci. USA 74: 1870–1874.
Lin, J., J.A. Miller, and E.C. Miller. 1977. 2,3-dihydro2-(guan-7-yl)-3-hydroxy-aflatoxin B1, a major acid hydrolysis product of aflatoxin B1-DNA or -ribosomal RNA adducts formed in hepatic microsome-mediated reactions and rat liver in vivo. Cancer Res. 37: 4430–4438.
Croy, R.G., J.M. Essigmann, V.N. Reinhold, and G.N. Wogan. 1978. Identification of the principal aflatoxin B1-DNA adduct formed in vivo in rat liver. Proc. Natl. Acad. Sci. USA 75: 1745–1749.
Singer, B. 1975. The chemical effects of nucleic acid alkylation and their relation to mutagenesis and carcinogenesis. In: Progress in Nucleic Acid Research and Molecular Biology, Volume XV. W.E. Cohn, ed. Academic Press: New York. pp. 219–284.
Wang, T.V., and P. Cerutti. 1980. Spontaneous reactions of aflatoxin B1 modified deoxyribonucleic acid in vivo. Biochemistry 19: 1692–1698.
Croy, R.G., and G.N. Wogan. 1981. Temporal patterns of covalent DNA adducts in rat liver after single and multiple doses of aflatoxin B1. Cancer Res. 41: 197–203.
Wang, T.V., and P. Cerutti. 1979. Formation and removal of aflatoxin B1-induced DNA lesions in epitheloid human lung cells. Cancer Res. 39: 5165–5170.
Croy, R.G., and G.N. Wogan. 1981. Quantitative comparison of covalent aflatoxin-DNA adducts formed in rat and mouse livers and kidneys. J. Natl. Cancer Inst. 66: 761–768.
Croy, R.G., J.E. Nixon, R.O. Sinnhuber, and G.N. Wogan. 1980. Investigation of covalent aflatoxin B1-DNA adducts formed in vivo in rainbow trout ( Salmo gairdneri) embryos and liver. Carcinogenesis 1: 903–909.
Autrup, H., J.M. Essigmann, R.G. Croy, B.F. Trump, G.N. Wogan, and C.C. Harris. 1979. Metabolism of aflatoxin B1 and identification of the major aflatoxin B1 adducts formed in cultured human bronchus and colon. Cancer Res. 39: 694–698.
Godoy, H.M., and G.E. Neal. 1976. Some studies on the effects of aflatoxin B1 in vitro on nucleic acid synthesis in the rat and mouse. Chem. Biol. Interact. 13: 257–277.
Wogan, G.N., S. Pagialunga, and P.M. Newberne. 1974. Carcinogenic effects of low dietary levels of aflatoxin B1 in rats. Food Cosmet. Toxicol. 12: 681–685.
Wogan, G.N. 1973. Aflatoxin carcinogenesis. In: Methods in Cancer Research, Volume VII. H. Busch, ed. Academic Press: New York. pp. 309–344.
McGuire, R.A. 1969. Factors affecting the acute toxicity of aflatoxin B1 in the rat and mouse. M.S. thesis. Massachusetts Institute of Technology, Cambridge, MA.
Akoa, M., K. Kuroda, and G.N. Wogan. 1971. Aflatoxin B1: The kidney as a site of action in the mouse. Life Sci. 10: 495–501.
Wales, J.H. R.O. Sinnhuber, J.D. Hendricks, J.E. Nixon, and T.A. Eisele. 1978. Aflatoxin B1-induction of hepatocellular carcinoma in the embryos of rainbow trout (Salmo gairdneri). J. Natl. Cancer Inst. 60: 1133–1139.
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© 1983 Plenum Press, New York
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Croy, R.G., Essigmann, J.M., Wogan, G.N. (1983). Aflatoxin B1: Correlations of Patterns of Metabolism and DNA Modification with Biological Effects. In: Langenbach, R., Nesnow, S., Rice, J.M. (eds) Organ and Species Specificity in Chemical Carcinogenesis. Basic Life Sciences. Springer, Boston, MA. https://doi.org/10.1007/978-1-4684-4400-1_3
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DOI: https://doi.org/10.1007/978-1-4684-4400-1_3
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