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Mutagenic Properties of Benzo(a)pyrene and Its Methylated Derivatives in Relation to the Molecular Mechanisms of Hydrocarbon Carcinogenesis¹

Department of Genetics, Institute of Cancer Research, Chester Beatty Research Institute, Royal Cancer Hospital, Fulham Road, London SW3 6JB, England

The carcinogen benzo(a)pyrene is mutagenic in Drosophila, although this activity appeared to require crucial conditions for the metabolic activation of the compound. The genetic properties of the hydrocarbon were substantially altered as a consequence of various methyl or methylol substitutions on its metabolically significant molecular sites: positions 1,3, and 6. The 3-methyl and 6-hydroxymethyl derivatives were more mutagenic than the parent hydrocarbon, and dimethyl substitution caused dramatic changes in this activity, the 3,6-compound being most effective; whereas its 1,6-analog was virtually inactive.

The mutagenicity of this chemical series also depended on the organization and physiological state of the biological targets, both at the cellular and genic levels. Variations occurred between derivatives as regards the patterns of yield of different mutational classes in the successive germ cell stages during spermatogenesis. Differences were also discernible in the selective mutagenicities of some compounds for the ribosomal RNA genes, as indicated by the bobbed/X chromosome mutability ratios. On the whole, however, these ratios were much lower than for other aromatic carcinogens but were of the same order as those associated with alkylation carcinogenesis.

The genetic and carcinogenic activities of the examined benzo(a)pyrenes were compared, and both phenomena were considered in relation to the molecular mechanisms proposed for their chemical reactivation. Evidence was adduced in favor of the suggestion that these compounds were metabolically converted into complex ionic species with multiple reactive centers, which could differentially attack the cellular macromolecules. The carcinogenically significant events appeared to involve reactions with DNA analogous to those responsible for alkylation mutagenesis.

¹ This work was supported by grants to the Chester Beatty Research Institute (Institute of Cancer Research: Royal Cancer Hospital) from the Medical Research Council and the Cancer Research Campaign.

Received 6/13/72. Accepted 10/23/72.