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Prostaglandin synthase-mediated metabolism of carcinogens and a potential role for peroxyl radicals as reactive intermediates

Journal Article · · Environmental Health Perspectives; (USA)
DOI:https://doi.org/10.1289/ehp.90885· OSTI ID:5718625
 [1]
  1. Vanderbilt Univ. School of Medicine, Nashville, TN (USA)
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Prostaglandin-H synthase is unique among enzymes of the plant and animal kingdom in its ability to biosynthesize and metabolize hydroperoxides. Higher oxidation states of the peroxidase oxidize reducing substrates to electron-deficient derivatives that react with macromolecular nucleophiles. In the case of aromatic amines, the electron-deficient derivatives are mutagenic to bacterial and mammalian cells. {beta}-Dicarbonyl compounds and retinoic acid are oxidized to carbon-centered radicals that react with O{sub 2} to form peroxyl free radicals. Peroxyl radicals are the most stable oxy radicals and are able to diffuse some distance from the site of their generation. Peroxyl radicals are also formed during lipid peroxidation and in the reaction of polyunsaturated fatty acid hydroperoxides with metal complexes and metalloproteins. Peroxyl radicals epoxidize isolated doubled bonds of compounds such as 7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene (BP-7,8-diol); 3,4-dihydroxy-3,4-dihydrobenzo(a)anthracene; and aflatoxin B{sub 1}. The epoxide products represent the ultimate carcinogenic forms of the respective compounds. Techniques for quantitating the extent of peroxidase dependent or peroxyl radical-dependent metabolism in vivo make use of differences in the structure or stereochemistry of reactive intermediates formed by peroxidases relative to cytochromes P-450. Differences in the relative amounts of hydrolysis products and DNA adducts derived from anti- and syn-dihydrodiolepoxides following application of BP-7,8-diol to mouse skin in vivo indicate peroxyl radicals play a significant role in metabolism of BP-7,8-diol in uninduced animals.
OSTI ID:
5718625
Journal Information:
Environmental Health Perspectives; (USA), Journal Name: Environmental Health Perspectives; (USA) Vol. 88; ISSN 0091-6765; ISSN EVHPA
Country of Publication:
United States
Language:
English

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Related Subjects

560300* -- Chemicals Metabolism & Toxicology
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
AFLATOXINS
ANTHRACENE
ANTIGENS
ARACHIDONIC ACID
AROMATICS
BENZOPYRENE
BIOCHEMISTRY
CARBOXYLIC ACIDS
CARCINOGENS
CHEMICAL REACTIONS
CHEMISTRY
CONDENSED AROMATICS
CYTOCHROME OXIDASE
ENZYMES
EPOXIDES
HAEM DEHYDROGENASES
HYDROCARBONS
LIGASES
MATERIALS
METABOLISM
MONOCARBOXYLIC ACIDS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
OXIDATION
OXIDOREDUCTASES
PEROXY RADICALS
PROSTAGLANDINS
RADICALS
REACTION INTERMEDIATES
STEREOCHEMISTRY
TOXIC MATERIALS
TOXINS