Synthesis and mutagenicity of 5-alkyl-substituted chrysene-1,2-diol-3,4-epoxides

Abstract

In order to explore the relationship between structure and mutagenicity of bay region diol-epoxides of chrysene substituted with an alkyl group in the bay region, we compared the mutagenicity in Salmonella typhimurium TA 100 of anti-1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydrochrysene with its 5-methyl, 5-ethyl and 5-propyl derivatives. The results showed that anti-1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene (7400 revertants/nmol) was the most mutagenic of these diol-epoxides followed by anti-1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydrochrysene and its 5-ethyl derivative (1100 revertants/nmol). The 5-propyl substituted diol-epoxide was inactive at the doses tested. The results demonstrate that steric factors are dominant in the expression of methylchrysene diol-epoxide mutagenicity in S. typhimurium and suggest that the molecular shape of the 5-methyl substituted diol-epoxide leads to a unique reaction with DNA associated with high mutagenicity and tumorigenicity.

Cytotoxicity and mutagenicity of 5-methylchrysene and its 1,2-dihydrodiol in V79MZ cells modified to express human CYP1A1 or CYP1B1, in the presence or absence of human GSTP1 coexpression

“…The environmental PAH 5MC is one of the most potent rodent carcinogens among the PAHs with an alkyl side group (Amin, 1985; Hecht, 1985), and hence was chosen for this study as a representative of this group along with its intermediate metabolite, 5MC-1,2-diol (Amin, 1988; Hecht, 1978). While V79MZ cells are insensitive to mutagenicity of the parent compound 5MC, expression of either hCYP1B1 or hCYP1A1 resulted in potent activation to highly mutagenic 5MC metabolites (Fig.…”

“…Vivid BOMCC substrate was purchased from Invitrogen. 5-Methylchrysene (5MC) was obtained from the National Cancer Institute (NCI) carcinogen repository (Chemsyn), Kansas City, MO and 5-methylchrysene-1,2-dihydrodiolol (5MC-1,2-diol) was synthesized by S. Amin as previously described (Amin, 1988). (Caution: 5MC and its metabolites described herein are potential chemical carcinogens and must be handled with caution as outlined in the NCI guidelines) .…”

Site-specific adducts derived from the binding of anti-5-methylchrysene diol epoxide enantiomers to DNA: Synthesis and characteristics

“…The molar extinction coefficient, e(260 nm) <* 9.8X10 4 M/cm of this oligonucleotide was estimated according to the methods of Warshaw et al (28). The racemic an/i-5-MeCDE was synthesized as described previously (29,30).…”

Solution Conformation of the (-)-trans-anti-5-Methylchrysene-dG Adduct opposite dC in a DNA Duplex: DNA Bending Associated with Wedging of the Methyl Group of 5-Methylchrysene to the 3'-Side of the Modification Site

“…A new structural effect in which the methyl group is wedged between adjacent base pairs and causes a bend at the lesion site has been established here. While the effects of stereochemistry of diastereomeric and chiral PAH diol epoxides can be one important determinant of biological activity (reviewed by Conney, 1982), there is no doubt that the presence of (and the site of substitution) of a methyl group in stereochemically identical positional isomers can have a profound effect on the tumorigenic (Hecht et al, 1987) and mutagenic characteristics (Melikian et al, 1988;Amin et al, 1986Amin et al, , 1988 of diol epoxide derivatives in this family of chrysene compounds. Enhanced tumorigenicity has been observed for a number of other PAH compounds in addition to chrysene when methylphenanthrene (LaVoie et al, 1982), methylbenz[a]anthracene (Wislocki et al, 1983), methylbenzo[a]pyrene (Iyer et al, 1980), and benz[a]anthracene (Slaga et al, 1979).…”

“…The tumorigenic activity of -5-MeCDE in newborn mice and on mouse skin (Hecht et al, 1980(Hecht et al, , 1985(Hecht et al, , 1987 and its mutagenic activity in Chinese hamster V79 cells (Brookes et al, 1986), in the 100 strain of Salmonella typhimurium (Amin et al, 1986(Amin et al, ,1988, and in the supF target gene of an SV40-based pS189 shuttle vector replicating in human cells (Bigger et al, 1990) have been studied. The (+)-anri-5-MeCDE enantiomer is significantly more tumorigenic than the (-)-enantiomer in the lung of newborn mice and in the mouse skin tumor model systems (Hecht et al, 1987;Melikian, 1988).…”