RADICAL CATIONS OF PAH IN CARCINOGENESIS AND METABOLISM

Project: Research project

Description

Metabolic activation of polycyclic aromatic hydrocarbons (PAH) can
be understood in terms of two main pathways: one-electron
oxidation to yield reactive intermediate radical cations and
monooxygenation to produce bay-region diol epoxides. Although
considerable data have been interpreted as evidence for bay-region
diol epoxides as the ultimate carcinogenic metabolites of the most
potent PAH, which include benzo(a)pyrene (BP), 7,12-
dimethylbenz(a)anthracene and 3-methylcholanthrene, substantive
results from carcinogenicity experiments do not support this
hypothesis. To gain more evidence about one-electron oxidation in
the metabolism, carcinogenesis and binding of PAH to DNA and
protein, we plan the following studies with BP and 6-CH3BP as
models for unsubstituted and methyl-substituted PAH. To
demonstrate that BP radical cations are involved in the formation
of 3- and 9-hydroxyBP, we will study the metabolism of 3- and 9-
FBP with rat liver microsomes and analyze the formation of the
respective hydroxy derivatives by high pressure liquid
chromatography. We will also investigate the ability of cysteine
to act as a trapping agent for BP reactive intermediates formed by
cytochrome P-450 and to reduce the binding of BP to DNA and
protein. We will determine the structure of BP-DNA and BP-protein
adducts formed by rat liver microsomes and nuclei to determine
whether or not binding involves the BP radical cation. To gain
evidence that the carcinogenicity of 6-FBP and the non-carcino-
genicity of 9-FBP are related to their radical cation chemistry,
we will a) determine the relative reactivity at C-6 of the radical
cation of 6-, 8-, and 9-FBP obtained by one-electron oxidation with
manganic acetate; b) compare the extent of binding of BP, 6-, 8-
and 9-FBP to DNA catalyzed by horseradish peroxidase (HRP),
prostaglandin H synthase (PHS) and rat liver microsomes; c)
identify the adducts formed when 6-FBP is bound to DNA by HRP, PHS
and microsomes. Finally, to study the activation of a methyl-
substituted PAH by one-electron oxidation, we will identify the
adducts formed when 6-CH3BP is bound to a) DNA by HRP, PHS and rat
liver microsomes; b) protein by rat liver microsomes; and c)
histones and DNA in rat liver nuclei. The results from this
project will provide further evidence on the central role of one-
electron oxidation in the metabolism, binding and carcinogenesis
of PAH.
StatusFinished
Effective start/end date9/25/888/31/95

Funding

  • National Institutes of Health: $132,661.00
  • National Institutes of Health
  • National Institutes of Health: $24,266.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

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Polycyclic Aromatic Hydrocarbons
Cations
Liver
Metabolism
Rats
DNA
Tumors
Horseradish Peroxidase
Derivatives
Prostaglandin-Endoperoxide Synthases
Oxidation
Electrons
Epoxy Compounds
Chemical activation
Methylcholanthrene
Benzo(a)pyrene
Histones
Proteins
Acetates
Metabolites

ASJC

  • Medicine(all)