The formation, stereostructure, and cellular reactions of the 7,8-diol-9,10-epoxide metabolites of the carcinogen benzo[a]pyrene have been examined after topical application of benzo[a]pyrene to the skin of mice. In this known target tissue, polymer adducts from diastereomeric diol epoxides, (+)-(7S, 8R, 9R, 10R) and (+)-(7R, 8S, 9R, 10R), were formed stereospecifically from their corresponding 7,8-dihydrodiols. Both diol epoxides bind with proteins, RNA, and DNA in vivo. For the nucleic acids, binding occurs preferentially at the 2-amino group of guanine in cellular RNA and DNA in vivo. Methods for establishing the structure of the cellular adducts as well as the possible biological implications of their formation are discussed.

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3 -Amino -1 -methyl -5H -pyrido[4,3 -blindole, 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.Carcinogenic chemicals produced by incomplete combustion processes represent a significant hazard to which we are exposed. The molecular mechanism(s) by which these chemicals initiate and promote the development of tumors has not been elucidated despite many years of intensive investigation, although it is now generally accepted that covalent reactions with critical cellular target molecules play an integral role in the process. Many carcinogens require metabolic activation prior to adduct formation (1, 2); due largely to the work of Miller and Miller (2,3) it is known that the activated species are electrophilic in nature. It has become increasingly clear that carcinogenic chemicals can generally also behave as mutagens (4), supporting the concept of somatic mutation as the basis of carcinogenesis (4-6).An active, and somewhat controversial, area of investigation has involved the correlation of the carcinogenic or mutagenic potential of several chemicals with their relative affinities for nucleic acids. For example, Brookes and Lawley (7) mutagen structurally reminiscent of 2-aminofluorene and reported to be identical with a product resulting from pyrolysis of tryptophan (19). In the present study, compound 1, and several synthetic analogs thereof, have been shown to be mutagenic toward Salmonella typhimurium only in the presence of a microsomal activating system. Remarkably, for these compounds there is a reasonable correlation between mutagenic activity and the extent of physicochemical interaction with calf thymus DNA. Discussed herein is the nature of this correlation and its possible implications for the mechanism of action of these species as mutagens.MATERIALS AND METHODS Synthesis of Test Substances. The syntheses of compounds 1 and 2 have been reported (20, 21). As will be described in detail elsewhere, compound 3 was prepared from 1 (acetic anhydride, pyridine, 25°C) as a white solid in high yield and then converted to 3-ethylamino-1-methyl-5H-pyrido[4,3-b]indole (4) by treatment with lithium aluminum hydride in tetrahydrofuran; both were characterized by UV, NMR, and mass spectrometry. Analogous acetylation of 4 and reductive treatment of the formed acetate afforded 3-(N,N-diethylamino)-1-methyl-5H-pyrido [4,3-b]indole (5). Deamination of I was effected by...