Benzo pyrene mutagenicity, human cell

J. D. Regan, A. A. Francis, W. C. Dunn, O. Hernandez, H. Yagi, and D. M. Jerina, Repair of DNA damaged by mutagenic metabolites of benzo(a)pyrene in human cells, Chem.-Biol. Interact. 20, 279-287 (1978). 

Durant and co-workers (1998) analyzed an organic extract of the NIST reference complex mixture SRM 1649 (see Box 10.3) using the same human cell line (hlAlv2) and bioassay-directed fractionation. In the nonpolar fraction, cy c 1 o pe n t a[ cz/ ] py re n e, benzo[a]-pyrene, and benzo[ b ]fl uo ran the ne were responsible for 7, 4, and 2%, respectively, of the total extract mutagenicity. Only one potent O-PAC mutagen was identified in the semipolar fraction, the ketone, 6H-benzo[cd ]pyren-6-one ( 0.5%) (see discussion in Section D.3). 

Busby, W. F., H. Smith, C. L. Crespi, and B. W. Penman, Mutagenicity of Benzo[ci]pyrene and Dibenzopyrenes in the Salmonella typhimurium TM677 and the MCL-5 Human Cell Forward Mutation Assays, Mutat. Res., 342, 9-16 (1995). 

Lo Jacono F, Stecca C, Duverger M. 1992. Mutagenic activation of benzo[a]pyrene by human red blood cells. Mutat Res 268(1 ) 21-26. 

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. 

The toxification of benzo[a]pyrene and most other polycyclic aromatic hydrocarbons to mutagenic intermediates by continuous cell lines has been reported dozens of times, whereas toxification of aflatoxin Bj to mutagenic intemediates in some cell lines does not occur.225 These data can be explained by the fact that the forms of P-450 necessary for polycyclic-hydrocarbon toxification remain in cultured primary and continuous cell lines, whereas the forms of P-450 responsible for the 2,3-oxide formation of aflatoxin Bj disappear rapidly in culture, for unknown reasons. Studies involving cultured human tissues may have this same major liability. The choice of cell culture for any particular compound therefore can be important. 

Tomkins DJ, Kwok SE, Douglas GR, et al. 1982. Sister chromatid exchange response of.human diploid fibroblasts and Chinese hamster ovary cells to dimethyinitrosamine and benzo(a)pyrene. Environ Mutagen 4 203-214. 

Work by Maher et al. (51) on the effect of UV irradiation on human fibroblasts has shown that cell survival is lower and mutation rates higher upon UV irradiation in DNA excision-repair-incompetent cells than in normal cells. Normal cells were also observed to survive a usually lethal and mutagenic UV dose upon being held in confluence (nondividing) for a period of time prior to assessment of survival and mutation rate. These results suggest that this recovery was a result of the increased time given DNA repair mechanisms to remove thymine dimers prior to replication. These workers have also demonstrated that the actual number of DNA alkylation sites removed from the DNA of benzo(a)pyrene exposed fibroblasts by repair mechanisms is directly related to cell survival (52). 

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