Mammalian cell carcinogenesis

Ansari RM, Hei TK. Effects of extremely low frequency magnetic fields (EMF) on radiation- and chemical-induced mutagenesis in mammalian cells. Carcinogenesis 2000 453(1) 1221—6. 

Epoxides are often encountered in nature, both as intermediates in key biosynthetic pathways and as secondary metabolites. The selective epoxidation of squa-lene, resulting in 2,3-squalene oxide, for example, is the prelude to the remarkable olefin oligomerization cascade that creates the steroid nucleus [7]. Tetrahydrodiols, the ultimate products of metabolism of polycyclic aromatic hydrocarbons, bind to the nucleic acids of mammalian cells and are implicated in carcinogenesis [8], In organic synthesis, epoxides are invaluable building blocks for introduction of diverse functionality into the hydrocarbon backbone in a 1,2-fashion. It is therefore not surprising that chemistry of epoxides has received much attention [9]. 

Moraes, E.C., Keyse, S.M. and Tyrrell, R.M. (1990). Mutagenesis by hydrogen peroxide treatment of mammalian cells a molecular analysis. Carcinogenesis 11, 283-293. 

Nassi-Calo, L., Mello-Filho, A.C. and Meneghini, R. (1989). 0-Phenanthroline protects mammalian cells from hydrogen peroxide-induced gene mutation and morphological transformation. Carcinogenesis 10, 1055-1057. 

Recent advances in PAH carcinogenesis research over the past decade have led to identification of diol epoxide metabolites as the principal active forms of the PAH investigated to date Q,2). Benzo-(a)pyrene (BP) has been most intensively investigated, and it has been demonstrated that a diol epoxide metabolite anti-BPDE is the active intermediate which binds covalently to DNA in human and other mammalian tissues 0,4). Anti-BPDE was also demonstrated to be a powerful mutagen in both bacterial and mammalian cells (15) These findings stimulated an outpouring of research directed towards elucidation of the molecular mechanism of PAH carcinogenesis. 

Hepatic peroxisome proliferation depends on a nuclear receptor, PPARa, to mediate these responses in mice, based on lack of response to peroxisome proliferators in PPARa-deficient mice. In one study with another peroxisome proliferator, WY-14,643, carcinogenesis was shown to be dependent on the same receptor. Oral administration of di(2-ethylhexyl) phthalate failed to elicit markers of peroxisome proliferation in PPARa-deficient mice, while the same treatment elicited this response in normal mice. Metabolites of di(2-ethylhexyl) phthalate caused activation of PPARa-mediated gene expression in mammalian cell co-transfection assays. Differences between responsive rodents and humans in various aspects of PPARa-mediated regulation of gene expression are consistent with the lack of activity of di(2-ethylhexyl) phthalate metabolites in hepatocyte cultures from 12 people studied to date. 

Barrett, J.C. and Elmore. E. (1984). Comparison of carcinogenesis and mutagenesis of mammalian cells in culture, in Handbook of Experimental Pharmacology, ANDREWS, L.S., Lorentzen, R.J., AND Flamm, W.D., Eds. (Springer-Verlag, Berlin). 

Fox, M. Brennand, J. (1980) Evidence for the involvement of lesions other than fV- -alkvlgua-nine in mammalian cell mutagenesis. Carcinogenesis, 1, 795-799... 

Zhitkovich A, Voitkun V, Costa M. 1995. Gluathione and free amino acids from stable complexes with DNA following exposure of intact mammalian cells to chromate. Carcinogenesis 16(4) 907-913. 

Boreiko CJ. 1985. Mechanistic Aspects of Initiation and Promotion in C-3H-10T-1-2 Cells. In Barrett JC, Tennant RW, eds. Carcinogenesis A comprehensive survey, Vol. 9. Meeting Mammalian cell transformation Mechanisms of carcinogenesis and assays for carcinogens, Research Triangle Park, NC. New York, NY Raven Press, 153-166. 

Suzuki K, Hei TK. 1996. Induction of heme oxygenase in mammalian cells by mineral fibers distinctive effect of reactive oxygen species. Carcinogenesis 17(4) 661-667. 

Landolph JR (1990) Neoplastic transformation of mammalian cells by carcinogenic metal compounds Cellular and molecular mechanisms. In Foulkes EC (ed.) Biological Effects of Heavy Metals. Metal Carcinogenesis, vol. II, pp. 1-18. Boca Raton, FL CRC Press. 

Benzo[a]pyrene has also been shown to affect immune responses to viral infection. Benzo[a]pyrene can reversibly inhibit the induction of viral interferon in 32 different mammalian cell lines but only in the presence of S9 metabolic activation (Hahon and Booth 1988). This inhibition must occur at an early level and not affect viral interferon interactions because the activity of exogenous interferon was unaffected. In addition, influenza virus multiplication was also inhibited by activated benzo[a]pyrene. Benzo[e]pyrene had no effect on interferon induction. The authors suggest that benzo[a]pyrene s inhibition of interferon induction may be an early step in compromising the host s immune function, thereby allowing the induction of carcinogenesis. 

ESCODD (2002) Comparative analysis of baseline 8-oxo-7,8-dihydroguanine in mammalian cell DNA, by different methods in different laboratories an approach to consensus. Carcinogenesis 23 2129-33... 

Mammalian cell tests are considered to be more relevant for mammalian carcinogenesis than are microbial or other nonmammalian tests because of the similarity of mammalian chromosomes and DNA repair and replication processes across species. Positive results in mammalian cells for a substance that is positive in bacterial cells ensure that the result seen in bacteria was not unique to the bacterial chromosome or bacterial metabolism. However, a negative result in mammalian cell tests would not necessarily negate the implications of a positive response in the bacterial test. 

Glatt, H Davis, W., Meinl, W., Hermersdorfer, H., Venitt, S. and Phillips, D.H. (1998) Rat, but not human, sulfotransferase activates a tamoxifen metabolite to produce DNA adducts and gene mutations in bacteria and mammalian cells in culture. Carcinogenesis, 19, 1709-1713. 

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