Reactivity and Tumorigenicity of Bay-Region Diol Epoxides Derived from Polycyclic Aromatic Hydrocarbons

  • D. M. Jerina
  • J. M. Sayer
  • S. K. Agarwal
  • H. Yagi
  • W. Levin
  • A. W. Wood
  • A. H. Conney
  • D. Pruess-Schwartz
  • W. M. Baird
  • M. A. Pigott
  • A. Dipple
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 197)

Abstract

The polycyclic aromatic hydrocarbons are a widespread class of environmental contaminants which express their tumorigenic activity through metabolic transformation to chemically reactive species which covalently modify cellular macromolecules. Ten years ago12 we proposed that bay-region diol epoxides are prime candidates for the ultimate carcinogenic metabolites of the carcinogenic hydrocarbons provided that these molecules contained a bay-region and were capable of being metabolically transformed to such diol epoxides. The noncarcinogen phenanthrene is the simplest hydrocarbon that contains a bay region, the sterically hindered, cup-shaped area between carbons-4 and -5 of the molecule. The metabolic transformation of this hydrocarbon3,4 into bay-region diol epoxides is illustrated in Figure 1. Initially the hydrocarbon is oxidized by the cytochrome P450 monooxygenase system to form a 1,2-oxide that is subsequently converted in the presence of microsomal epoxide hydrolase to a trans-1,2-dihydrodiol by allylic attack of water. Although many arene oxides show a marked tendency to isomerize spontaneously to phenols.5 epoxide hydrolase is often highly competitive in intercepting these reactive species. The 1,2-dihydrodiol is subject to further attack by the cytochrome P450 system to form a mixture of diastereomerically related diol epoxides in which the benzylic hydroxyl group is either cis (isomer-1 series) or trans (isomer-2 series) to the epoxide oxygen. One of the interesting features of these diol epoxides is that the isomer-1 series shows a slight preference for the conformation in which the hydroxyl groups are pseudoaxial whereas the isomer-2 series shows a marked preference for the conformation in which these groups are pseudo-equatorial (vide NMR).6-8These conformational preferences can be altered through structural variations as will be discussed later.

Keywords

Hydrocarbon Nucleoside Tritium Sorbitol Guanine 

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Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • D. M. Jerina
    • 1
  • J. M. Sayer
    • 1
  • S. K. Agarwal
    • 1
  • H. Yagi
    • 1
  • W. Levin
    • 2
  • A. W. Wood
    • 2
  • A. H. Conney
    • 2
  • D. Pruess-Schwartz
    • 3
  • W. M. Baird
    • 3
  • M. A. Pigott
    • 4
  • A. Dipple
    • 4
  1. 1.The National Institutes of Health, NIADDKBethesdaUSA
  2. 2.Roche Institute of Molecular BiologyNutleyUSA
  3. 3.Department of Medicinal Chemistry and PharmacognosyPurdue UniversityW. LafayetteUSA
  4. 4.LBI-Basic Research ProgramNCI-Frederick Cancer Research FacilityFrederickUSA

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