Complex Metabolic Activation Pathways of Polycyclic Aromatic Hydrocarbons: 3-Hydroxy-trans-7,8-Dihydroxy-7,8-Dihydrobenzo[a]Pyrene as a Proximate Mutagen of 3-Hydroxybenzo[a]Pyrene

  • Hansruedi Glatt
  • Paul C. Hirom
  • Charles A. Kirkby
  • Odartey Ribeiro
  • Albrecht Seidel
  • Franz Oesch

Abstract

3-Hydroxybenzo[a]pyrene (3-OH-BP) is a major metabolite of benzo[a]pyrene (BP) in various systems. Metabolites of 3-OH-BP, formed by liver enzymes, bind to DNA1,2 and are mutagenic3,4. However, the active species have not yet been identified. Administration of 3-OH-BP to rats results in the excretion of sulfate and glucuronic acid conjugates of 3-hydroxy-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (3-OH-BP-7,8-diol) (Fig. 1) as major metabolites in the bile5. The hydroxyl groups of this triol are structurally superimposable to those of 9-hydroxy-trans-1,2-dihydroxy-1,2-dihydrochrysene (9-hydroxychrysene-1,2-diol, Fig. 1), which is a metabolite of chrysene6,7 and a potent promutagen8,9. 9-Hydroxychrysene-1,2-diol is activated by mammalian enzymes to anti-chrysene-1,2-diol-3,4-oxide7, which is chemically more reactive, is more mutagenic in bacterial and mammalian cells and is more potent in the malignant transformation of C3H10T1/2 cells than is the simple bay-region diol-epoxide of chrysene8,9. Furthermore, after application of chrysene to mouse skin, a target organ for carcinogenicity, this triol-epoxide forms a major type of DNA-adduct7,10. The higher chemical reactivity and biological activity of 9-hydroxychrysene-1,2-diol-3,4-oxides as compared to the chrysene-1,2-diol-3,4-oxides may be explained, and were predicted, on electronic grounds11: the hydroxyl group may resonance-stabilize the bay-region carbonium ion that results from opening of the oxirane ring. Analogous resonance stabilization is expected to occur with the carbonium ions formed from 3-0H-BP-7,8-diol-9,10-oxides11. Therefore, it was of interest to investigate the novel, secondary BP metabolite, 3-OH-BP-7,8-diol, for mutagenity.

Keywords

Polycyclic Aromatic Hydrocarbon Mouse Skin High Chemical Reactivity Glucuronic Acid Conjugate Mutagenic Potency 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer Science+Business Media New York 1988

Authors and Affiliations

  • Hansruedi Glatt
    • 1
  • Paul C. Hirom
    • 2
  • Charles A. Kirkby
    • 2
  • Odartey Ribeiro
    • 2
  • Albrecht Seidel
    • 1
  • Franz Oesch
    • 1
  1. 1.Institute of ToxicologyUniversity of MainzMainzFederal Republic of Germany
  2. 2.Department of BiochemistrySt. Mary’s Hospital Medical SchoolLondonUK

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