The reaction of a 3-methylcholanthrene diol epoxide with DNA in relation to the binding of 3-methylcholanthrene to the DNA of mammalian cells

Abstract

DNA prelabelled in the purine or pyrimidine bases was reacted with anti-7,8-epoxy-trans-9,10-dihydroxy-7,8,9,10-tetra-hydro-3-methylchol ant hrene (anti-3MCDE). Enzymic degradation and column chromatography allowed the isolation of a number of hydrocarbon--nucleoside derivatives. The major product was shown to result from reaction with the 2-amino-group of guanine, but minor products containing guanine, adenine and cytosine were also obtained. One of the minor products, probably resulting from reaction at N7-guanine, led to rapid depurination. Anti-3MCDE was an efficient mutagen at the hprt-locus of V79 cells even at low doses which caused no cytotoxicity. In all the above properties anti-3MCDE closely resembled the anti-diol-epoxide of benzo[a]-pyrene. A similar study of DNA derived from mouse embryo cells which had been exposed to tritium labelled 3-methylcholanthrene (3MC) yielded a series of nucleoside adducts, only a minority of which were derived by reaction of anti-3MCDE with DNA. Two major in vivo products were shown to derive from 3MC alcohols, particularly 3-hydroxymethyl-cholanthrene, and probably involved both syn and anti-diol-epoxide metabolites.