Autoxidation of 6-hydroxybenzo[a]pyrene and 6-oxobenzo[a]pyrene radical, reactive metabolites of benzo[a]pyrene

Lorentzen, Ronald J.; Caspary, William J.; Lesko, Stephen A.; Ts’o, Paul O. P.

doi:10.1021/bi00689a007

Cited by 139 publications

(29 citation statements)

References 23 publications

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“…Metabolism of PAHs through one electron oxidation resulting in reactive free radical intermediates that can react with DNA to form DNA covalent adducts has also been reported (28)(29)(30)(31)(32) (Figure 2). Due to differences in mechanisms of metabolic activation, the ultimate carcinogenic metabolites or intermediates as well as the types of DNA adducts formed from the diolepoxide formation or from the free radical generation are different.…”

Section: A Mammalian Metabolic Activation Of Pahsmentioning

confidence: 78%

Environmental Carcinogenic Polycyclic Aromatic Hydrocarbons: Photochemistry and Phototoxicity

2002

Journal of Environmental Science and Health, Part C

340

252

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Section: A Mammalian Metabolic Activation Of Pahsmentioning

confidence: 78%

Environmental Carcinogenic Polycyclic Aromatic Hydrocarbons: Photochemistry and Phototoxicity

2002

Journal of Environmental Science and Health, Part C

340

252

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“…6-Hydroxy-BaP is not detected as a stable metabolite of BaP, and Nagata et al were the first to show that its presence could be detected by observation of the EPR signal of the 6-oxy-BaP radical in rat liver homogenate metabolism of BaP (3,42). Ts'o et al (8,9) showed that the EPR signal obtained with BaP is identical to that obtained from chemical and enzymatic oxidation of 6-hydroxy-BaP. It was also shown that the 6-hydroxy-BaP was the precursor of most, if not all, of the BaP-diones (1,6-, 6,12-, and 3,6-) formed during the metabolism of BaP (9).…”

Section: Oxygenated Bap Radicalsmentioning

confidence: 87%

“…The free-radical or one-electron oxidation pathway involves the enzymatic formation of 6-hydroxy-BaP via a direct oxygen insertion mediated by cytochrome-P-450, or possibly via the reaction of the enzymatically formed BaP cation radical with water. The 6-hydroxyBaP is then rapidly oxidized in several one-electron steps via an intermediate radical identified as 6-oxyBaP, (the phenoxy radical derived from 6-hydroxyBaP), to produce a mixture of 1,6-,3,6-, and 6,12-BaPdiones (3,8,9,11). 6-Hydroxy-BaP is not detected as a stable metabolite of BaP, and Nagata et al were the first to show that its presence could be detected by observation of the EPR signal of the 6-oxy-BaP radical in rat liver homogenate metabolism of BaP (3,42).…”

Section: Oxygenated Bap Radicalsmentioning

confidence: 99%

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Free Radicals of Benzo(a)pyrene and Derivatives

Sullivan¹

1985

Environmental Health Perspectives

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“…The production of DNA adducts, as determined by the radioactivity bound to the DNA, was also proportional to the concentration of B[a]P to which the cells were exposed (Fig. 1) (25). In a system in which two types of active oxygens, hydrogen peroxide and superoxide anion, are formed, a further reaction leading to the generation of a more reactive species of free radical, the hydroxyl radical, is expected via a Haber-Weiss type of reaction (26).…”

Section: Resultsmentioning

confidence: 94%

Production of oxidative DNA damage during the metabolic activation of benzo[a]pyrene in human mammary epithelial cells correlates with cell killing.

Leadon

Stampfer

Bartley

1988

Proc. Natl. Acad. Sci. U.S.A.

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We have studied the generation of reactive oxygen species during the metabolism of a carcinogen, benzo [a]pyrene, by human mammary epithelial cells. We have quantitated the production of one type of oxidative DNA damage, thymine glycols, by using a monoclonal antibody specific to this base modification. Thymine glycols were produced in DNA in a dose-dependent manner after exposure of human mammary epithelial cells to benzo[alpyrene. The number of thymine glycols formed in the DNA was similar to that of 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[ajpy-rene covalently bound to the DNA. Exposure of cells to the carcinogen in the presence of superoxide dismutase, which reduces superoxide anions, inhibited the production of thymine glycols and increased cell survival but had little effect on adduct formation. At equitoxic doses, =10-fold more thymine glycols were formed after exposure to benzo[alpyrene than to yirradiation. Thymine glycols, produced by either agent, were efficiently removed from the DNA of the cells. Since thymine glycols represent only a portion of the oxidative damage possibly produced, our results indicate that the total amount of oxidative damage induced during the exposure of human mammary epithelial cells to benzo [a]pyrene greatly exceeds the amount produced by direct adduct formation and that this indirect damage plays an important role in the cytotoxicity ofgens, it is important to identify the primary DNA lesions produced directly by adduct formation and indirectly by free radicals.One product that is formed in DNA as a consequence of chemical oxidation or ionizing radiation is thymine glycol (13,14). A sensitive immunoassay for thymine glycols has been developed with a monoclonal antibody to this product in DNA (15). By using this methodology, thymine glycols have been detected in DNA after treatment of cultured human fibroblasts with ionizing radiation, 254-nm ultraviolet light, and an active metabolite of the carcinogen 2-naphthylamine (16,17). We have used this method to determine whether reactive oxygen species are being produced during the metabolism of B[a]P by HMEC and what role these reactive oxygen species play in cellular toxicity.Our results show that: (i) thymine glycols are produced in DNA in a dose-dependent manner at levels comparable to the amount of B[a]P diol epoxide covalently bound to DNA adducts after exposure of HMEC to B[a]P; (ii) the production of thymine glycols, but not that of B[a]P adducts, is reduced if superoxide dismutase (SOD) is present at the time of treatment; (iii) survival is increased if SOD is present during treatment with B[a]P; (iv) at equitoxic doses, 10-fold more thymine glycols are produced after B[a]P treatment than after ionizing radiation.There is increasing evidence implicating the involvement of free radicals, particularly those derived from molecular oxygen, in many stages of chemical carcinogenesis (1, 2). Active oxygens and the ensuing lipid peroxidations could affect carcinogenic processes in at least two ways: (i) by causi...

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Autoxidation of 6-hydroxybenzo[a]pyrene and 6-oxobenzo[a]pyrene radical, reactive metabolites of benzo[a]pyrene

Cited by 139 publications

References 23 publications

Environmental Carcinogenic Polycyclic Aromatic Hydrocarbons: Photochemistry and Phototoxicity

Environmental Carcinogenic Polycyclic Aromatic Hydrocarbons: Photochemistry and Phototoxicity

Free Radicals of Benzo(a)pyrene and Derivatives

Production of oxidative DNA damage during the metabolic activation of benzo[a]pyrene in human mammary epithelial cells correlates with cell killing.

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