| Autor: |
Stansbury KH; Department of Pharmacology, University of Kentucky, Lexington 40506., Flesher JW, Gupta RC |
| Jazyk: |
angličtina |
| Zdroj: |
Chemical research in toxicology [Chem Res Toxicol] 1994 Mar-Apr; Vol. 7 (2), pp. 254-9. |
| DOI: |
10.1021/tx00038a019 |
| Abstrakt: |
Three different pathways have been proposed for the metabolic activation of the ubiquitous polycyclic aromatic hydrocarbon, benzo[a]pyrene (BP). The most widely accepted activation mechanism is based on ring oxidation to diol epoxides; the other two relatively less studied pathways involve radical cation formation and benzylic electrophilic ester formation arising from a chain of substitution reactions. The present study was undertaken to test for the existence of the latter mechanism in vivo. Female Sprague-Dawley weanling rats were injected subcutaneously with 320 mumol of BP/kg body weight, and the formation of DNA adducts was examined. 32P-Postlabeling analysis of the subcutaneous tissue DNA under newly developed chromatography conditions exhibited two sets of adduct profiles: one resulting from alkyl substitution and the other from ring oxidation. One major and two minor aralkyl-DNA adducts were detected. The relative adduct labeling (adducts/10(10) nucleotides) remained constant at around 2 during the first 5 days of treatment and then increased to 6.4 +/- 2.6 at day 7. The corresponding total values of the known ring oxidation (e.g., diol epoxide) adducts were 15-50 times higher. When animals were injected with 6-methyl-BP, 6-(hydroxymethyl)-BP, and 6-(acetoxymethyl)-BP, the known or proposed intermediates in the benzylic ester pathway, each of these and the parent compound showed chromatographically identical profiles of aralkyl-DNA adducts. Cochromatography in multiple solvents of these in vivo adducts with standards prepared by reaction of 6-(bromomethyl)-BP with individual nucleotides showed that the predominant in vivo aralkyl-DNA adduct was derived from guanine while the second major adduct was from adenine.(ABSTRACT TRUNCATED AT 250 WORDS) |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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