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BIOTRANSFORMATION OF TRANS-4,5-DIHYDROXY-4,5-DIHYDROBENZO[A]PYRENE TO BENZO[A]PYRENE-BIS-DIOLS AND DNA ADDUCTS BY INDUCED RAT LIVER MICROSOMES
Citation:
Padgett, W. T., C. R. Davis, G. R. Lambert, G B. Nelson, J A. Ross, M. Yacopucci, AND S Nesnow. BIOTRANSFORMATION OF TRANS-4,5-DIHYDROXY-4,5-DIHYDROBENZO[A]PYRENE TO BENZO[A]PYRENE-BIS-DIOLS AND DNA ADDUCTS BY INDUCED RAT LIVER MICROSOMES. CHEMICAL RESEARCH IN TOXICOLOGY. American Chemical Society, Washington, DC, 13(11):1125-1134, (2001).
Description:
The biotransformation of (+)-trans-4,5-dihydroxy-4,5-dihydrobenzo[a]pyrene trans-B[a]P-4,5-diol), the K-region dihydrodiol of B[a]P, by B-naphthoflavone (BNF)-induced rat liver microsomes was studied. Trans-B[a]P-4,5-diol was metabolized to six major products as characterized by NMR, MS, and UV spectroscopy, and all were identified as bis-diols: two diastereomers of trans,trans-
4,5:7,8-tetrahydroxy-4,5:7,8-tetrahydrobenzo[a]pyrene (trans,trans-B[a]P-4,5:7,8-bis-diol), two diastereomers of trans,trans-4,5:9,10-tetrahydroxy-4,5:9,10-tetrahydrobenzo[a]pyrene (trans,trans-B[a]P-4,5:9,10-bis-diol), and two diastereomers of the somewhat unusual trans,trans-1,2:4,5-tetrahydroxy-1.2:4,5-tetrahydrobenzo[a]pyrene (trans,trans-B[a[P-1,2:4,5- bis-diols). BNF-induced rat liver microsomes also metabolized B[a]P to the same trans-B[a]P-4,5-diol-derived bis-diols. The ability of trans-B[a]P-4,5-diol to form DNA adducts was investigated using 32P-postlabeling techniques specifically designed to detect stable polar DNA adducts. Four DNA adducts were detected after microsomal activation of trans-B[a]P- 4,5-diol with calf thymus DNA. Further analyses indicated that each of these stable polar DNA adducts was derived from the further metabolic activation of the transs,trans-B[a]P-4,5:7,8-
bis-diols. We conclude that trans-B[a]P-4,5-diol can be metabolized to a series of B[a]P- bis-diols, and can also be metabolically activated to form stable polar DNA adducts. The trans,trans-B[a]P-4,5:7,8-bis-diols were shown to be metabolic intermediates in the formation of these DNA adducts.
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