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Biological Reactive Intermediates III pp 11–30Cite as

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

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Part of the book series: Advances in Experimental Medicine and Biology ((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 ago1’2 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.

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Authors and Affiliations

  1. The National Institutes of Health, NIADDK, Bethesda, MD, USA

    D. M. Jerina, J. M. Sayer, S. K. Agarwal & H. Yagi

  2. Roche Institute of Molecular Biology, Nutley, NJ, USA

    W. Levin, A. W. Wood & A. H. Conney

  3. Department of Medicinal Chemistry and Pharmacognosy, Purdue University, W. Lafayette, IN, USA

    D. Pruess-Schwartz & W. M. Baird

  4. LBI-Basic Research Program, NCI-Frederick Cancer Research Facility, Frederick, MD, USA

    M. A. Pigott & A. Dipple

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Editor information

Editors and Affiliations

  1. Thomas Jefferson University, Philadelphia, Pennsylvania, USA

    James J. Kocsis

  2. Medical University of South Carolina, Charleston, South Carolina, USA

    David J. Jollow

  3. Rutgers University, Piscataway, New Jersey, USA

    Charlotte M. Witmer  & Robert Snyder  & 

  4. University of Maryland, College Park, Maryland, USA

    Judd O. Nelson

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© 1986 Plenum Press, New York

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Jerina, D.M. et al. (1986). Reactivity and Tumorigenicity of Bay-Region Diol Epoxides Derived from Polycyclic Aromatic Hydrocarbons. In: Kocsis, J.J., Jollow, D.J., Witmer, C.M., Nelson, J.O., Snyder, R. (eds) Biological Reactive Intermediates III. Advances in Experimental Medicine and Biology, vol 197. Springer, Boston, MA. https://doi.org/10.1007/978-1-4684-5134-4_2

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