Synthesis, in vitro metabolism, mutagenicity, and DNA-adduction of naphtho[1,2-e]pyrene

Literature data, although limited, underscore the contribution of C₂₄H₁₄ polycyclic aromatic hydrocarbons to the biological activity of the extracts of complex environmental samples. However, little attention has been given to naphthopyrene (NP) isomers due to lack of synthetic standards and, therefore, lack of studies aimed at unequivocal identification of C₂₄H₁₄ isomers in environmental samples. We hypothesize that naphtho[1,2-e]pyrene (N[1,2-e]P), having a fjord region and a bay region might be a potent mutagen. To test our hypothesis, we synthesized N[1,2-e]P by Suzuki reaction and examined its in vitro metabolism with the S9 fraction from phenobarbital/β-naphthoflavone-induced rat liver homogenates. We have tentatively identified its K-region diol as the major metabolite and a fjord region dihydrodiol as minor metabolite. Contrary to our hypothesis, N[1,2-e]P was not mutagenic in S. typhimurium strain TA 100 and did not induce morphological cell transformation in mammalian cells. Its metabolite, 11,12-dihydroxy-11,12-dihydro-N[1,2-e]P was a weak mutagen. The reaction of calf thymus DNA with N[1,2-e]P-11,12-diol13,14-epoxide showed that it reacts predominately with the exocyclic amino group of adenine.