Synthesis, in vitro metabolism, cell transformation, mutagenicity, and DNA adduction of dibenzo[c,mno] chrysene

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Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants. Due to its structural similarity with the potent carcinogen dibenzo [a,l] pyrene (DB [a,l]P) and because of its environmental presence, dibenzo[c,mno]chrysene (naphtho[1,2-a]pyrene, N[1,2-a]P) is of considerable research interest. We therefore developed an efficient synthesis of N[1,2-a]P, and examined its in vitro metabolism by male Sprague Dawley rat liver S9 fraction. Its mutagenic activity in S. typhimurium TA 100 and its morphological cell transforming ability in mouse embryo fibroblasts were evaluated. On the basis of spectral analyses, the in vitro major metabolites were identified as the fjord region dihydrodiol trans-9,10-dihydroxy-9,10- dihydro-N[1,2-a]P (N[1,2-a]P-9,10-dihydrodiol), the K-region diols N[1,2-a]P-4,5-dihydrodiol and N[1,2-a]P-7,8-dihydrodiol, and also the 1-, 3-, and 10-hydroxy-N[1,2-a]P; the structure of N[1,2-a]P-9,10-dihydrodiol was also confirmed by independent synthesis. In assays with S. typhimurium TA 100, N[1,2-a]P-9,10-dihydrodiol was half as mutagenic as (±)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (B[a]P-7,8-dihydrodiol) at ≥ nmol/plate. N[1,2-a]P-9,- 10-dihydrodiol was much more mutagenic than N[1,2-a]P at all dose levels, suggesting that the N[1,2-a]P-9,10-dihydrodiol is the likely proximate mutagen of N[1,2-a]P. Evaluation of morphological cell transformation in C3H10T1/2C18 mouse embryo fibroblasts revealed that N[1,2-a]P was comparable to B[a]P. We further examined the pattern of in vitro adduct formation between calf thymus DNA and (±)-anti-9,10-dihydroxy-9,10-dihydro-11,12-epoxy- 9,10,11,12-tetrahydro-N[1,2-a]P (N[1,2-a]PDE) and found that dG-adduct formation is 2.9-fold greater than dA-adduct formation. On the basis of our results and those reported in the literature, our working hypothesis is that N[1,2-a]P may be added to the list of potent carcinogens that includes DB [a,l]P. This hypothesis is currently being tested in our laboratory.

Original languageEnglish (US)
Pages (from-to)964-971
Number of pages8
JournalChemical research in toxicology
Issue number7
StatePublished - 2002

All Science Journal Classification (ASJC) codes

  • Toxicology


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