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SYNTHESIS, IN VITRO METABOLISM, CELL TRANSFORMATION, MUTAGENICITY, AND DNA ADDUCTION ON NAPHTHO[1,2-A]PYRENE
Citation:
Desai, D., A. K. Sharma, J. Lin, J. Krzeminski, K ElBayoumy, M Pimentel, S Nesnow, S. Amin, AND A. K. Sharma. SYNTHESIS, IN VITRO METABOLISM, CELL TRANSFORMATION, MUTAGENICITY, AND DNA ADDUCTION ON NAPHTHO[1,2-A]PYRENE. CHEMICAL RESEARCH IN TOXICOLOGY 15(7):964-971, (2002).
Description:
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 naphtho[1,2- a]pyrene (N[1,2-a]P) is of considerable research interest. We therefore developed an efficient synthesis of N[l ,2-a ]P , and examined its in vitro metabolism metabolic activation by 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 major metabolites were identified as the fjord region dihydrodiol trans-9,10-dihydroxy-9,10-dihydro-N[l,2-a]P (N[1,2-a]P-9,10-dihydrodiol), the K-region diols N[I,2-a]P-4,5-dihydrodiol and N[I,2-a]P-7,8-dihydrodiol, as well as 1-,3-, and 10-hydroxy-substituted N[I,2-a]P; the structure of N[I,2-a]P-9,10-dihydrodiol was also confirmed by independent synthesis. In assays with S. typhimurium TA 100, N[I,2-a]P-9,10-dihydrodiol was twice as mutagenic as (?) trans-7,8-dihydroxy-7,8-dihydro- benzo[a]pyrene (B[a]P-7,8-dihydrodiol) at 4 nmol/plate. N[I,2-a]P-9,10-diol 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 C3H10Tl/2C18 mouse embryo fibroblasts revealed that N[I,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[I,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[I,2-a]P may be added to the list of potent carcinogens that includes DB[a,/]P. This hypothesis is currently being tested in our laboratory.