Metabolism of benzo(a)pyrene-3,6-quinone and 3-hydroxybenzo(a)pyrene in liver microsomes from 3-methylcholanthrene-treated rats

Lind, Christina; Vadi, Helena; Ernster, Lars

doi:10.1016/0003-9861(78)90256-4

Cited by 112 publications

(15 citation statements)

References 33 publications

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“…However, it has been claimed that simple hydroquinones are less reactive than semiquinone radicals and more easily eliminated from the cell as conjugates (Lind, 1985). QAO has been reported to protect cells against quinoneinduced cell necrosis (Benson et al, 1980;Lind et al, 1978;Momson et al, 1984;Thor et al, 1982) and carcinogenicity (Ames, 1983;Mohandas et al, 1986;Prochaska et al, 1985;Talalay and Benson, 1982) by reducing the concentration of free quinone available for single-electron reduction.…”

Section: Nad(p)h:(quinone-acceptor)oxidoreductase (Qao Ecmentioning

confidence: 99%

Cytosolic NAD(P)H:(Quinone‐acceptor)oxidoreductase in human normal and tumor tissue: Effects of cigarette smoking and alcohol

Schlager

Powis

1990

Intl Journal of Cancer

226

159

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NAD(P)H:(quinone-acceptor)oxidoreductase (QAO), previously known as DT-diaphorase, catalyzes the reduction of quinones to hydroquinones. Enhanced activity of the enzyme has been suggested to protect cells against the cellular toxicity and carcinogenicity of quinones, but may activate some cytotoxic anti-tumor quinones. Cytosolic levels of QAO, carbonyl reductase (CR) and total quinone reductase activity have been measured in normal and tumorous human tissues. QAO was the major component of the total cytosolic quinone reductase activity in all the tissues investigated. CR represented 10 to 28% of the total cytosolic quinone reductase activity in normal tissue. Normal tissue QAO was high in the stomach and kidney, and lower in the lung, liver, colon and breast. Primary tumor from lung, liver, colon and breast had elevated levels of QAO compared to normal tissue, while tumor from kidney and stomach had lower levels. CR was not significantly altered in tumor tissue, except in the case of lung and colon tumor which showed an increase compared to normal tissue. A major determinant of the variability of human lung tumor QAO was the cigarette-smoking history of the donor. Non-smokers and past smokers had high levels of tumor QAO compared to normal tissue. Smokers had levels of tumor QAO that were not significantly different from those of normal tissue QAO. Smokers had a small increase in normal lung QAO compared to non-smokers. Alcohol use was associated with an increase in lung tumor QAO but had no effect on QAO in normal lung. The function of QAO in tumors is not known but the elevated activity of QAO in some tumors and the apparent depressant effect of smoking could influence the response of these tumors to quinone drugs or toxic agents that are metabolized by QAO.

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Section: Nad(p)h:(quinone-acceptor)oxidoreductase (Qao Ecmentioning

confidence: 99%

Cytosolic NAD(P)H:(Quinone‐acceptor)oxidoreductase in human normal and tumor tissue: Effects of cigarette smoking and alcohol

Schlager

Powis

1990

Intl Journal of Cancer

226

159

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“…The 6-hydroxy-BP radical has furthermore been shown to be chemically reactive and to bind covalently to polynucleotides [ 191. The isomeric BP-quinones form conjugates with glutathione (see above), or they can be reduced and then conjugated with, for example, D-glucuronic acid [27,28]. If these various observations are applied to the present results, the metabolic scheme in fig.3 is obtained.…”

Section: Discussionmentioning

confidence: 74%

Oxygenation of benzo[a]pyrene by plant microsomal fractions

Trenck

Sandermann

1980

FEBS Letters

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“…Quinone reductase is unusual among flavoproteins in that it promotes obligatory two-electron reductions of quinones (45), thus diverting quinones from oxidative cycling and preparing them for conjugation with glucuronic acid (13,46,47 For these reasons, measurement of the cytosolic levels of quinone reductase of Hepa 1c1c7 hepatoma cells in culture provides a versatile, simple, and reliable method for identifying chemoprotective agents and for studying the mechanism of induction of chemoprotective enzymes.…”

Section: Discussionmentioning

confidence: 99%

Induction of NAD(P)H:quinone reductase in murine hepatoma cells by phenolic antioxidants, azo dyes, and other chemoprotectors: a model system for the study of anticarcinogens.

Long

Prochaska

Talalay³

1986

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

121

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Exposure of murine hepatoma (Hepa lclc7) cells to a variety of chemical agents known to protect animals against the neoplastic, mutagenic, and other toxic effects of chemical carcinogens results in dose-and time-dependent inductions of NAD(P)H:quinone reductase (EC 1.6.99.2). This enzyme protects against quinone toxicity by promoting obligatory two-electron reductions that divert quinones from oxidative cycling or direct interactions with critical nucleophiles. Quinone reductase levels are stable in culture, are easily measured, and are useful markers for the inductive effects of chemoprotective agents. The Hepa lclc7 system responds to chemoprotective compounds such as phenolic antioxidants {e.g., BHA [3(2)-tert-butyl-4-hydroxyanisole], BHT (3,5-ditert-butyl-4-hydroxytoluene), and tert-butylhydroquinone}, lipophilic azo dyes belonging to the 1,1'-azonaphthalene, Sudan I (1-phenylazo-2-naphthol), and Sudan m [1-(4-phenylazophenylazo)-2-naphtholl families, polycyclic aromatic hydrocarbons, coumarin and various other lactones, flavonoids, and certain sulfur compounds (e.g., benzylisothiocyanate, dithiolthiones, and dithiocarbamates), all of which are recognized enzyme inducers and chemoprotectors in vivo. Quinone reductase induction in Hepa lclc7 cells therefore provides a simple, versatile, and reliable system for the evaluation of the potency, kinetics, and mechanism of action of anticarcinogens.An astonishing variety of structurally unrelated compounds, including phenolic antioxidants, coumarins, azo dyes, flavonoids, polycycic aromatics, and certain sulfur compounds, protect laboratory animals against the neoplastic, mutagenic, and other toxic effects of chemical carcinogens (1, 2). Clarification of the molecular mechanisms underlying these protective actions is of importance in devising strategies for protecting man against cancer. Much evidence indicates that protection by these agents depends on altering the metabolism of carcinogens (3, 4). Some protectors (e.g., polycyclic hydrocarbons, 2,3,7,8-tetrachlorodibenzo-p-dioxin, and azo dyes) are potent inducers of both phase I and phase II drug-metabolizing enzymest, whereas other protective agents (e.g., phenolic antioxidants) induce phase II enzymes only (for review, see ref.3). Although the balance between these two types of enzymes required for protective action remains unclear, current evidence indicates that induction of such phase II enzymes as glutathione Stransferases, quinone reductase, and epoxide hydrolase is important for protection (1)(2)(3)(4)(6)(7)(8).We have developed a murine hepatic cell culture system (Hepa lclc7) that mimics many animal tissues in responding to a wide variety of chemoprotective agents by induction of cytosolic quinone reductase [NAD(P)H:(quinone-acceptor) oxidoreductase, EC 1.6.99.2; also known as menadione reductase, DT diaphorase, or vitamin K reductase]. These cells are a suitable model for studying chemoprotection because (i) they retain many characteristics ofnormal tissues, particularly the capacity for carci...

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Metabolism of benzo(a)pyrene-3,6-quinone and 3-hydroxybenzo(a)pyrene in liver microsomes from 3-methylcholanthrene-treated rats

Cited by 112 publications

References 33 publications

Cytosolic NAD(P)H:(Quinone‐acceptor)oxidoreductase in human normal and tumor tissue: Effects of cigarette smoking and alcohol

Cytosolic NAD(P)H:(Quinone‐acceptor)oxidoreductase in human normal and tumor tissue: Effects of cigarette smoking and alcohol

Oxygenation of benzo[a]pyrene by plant microsomal fractions

Induction of NAD(P)H:quinone reductase in murine hepatoma cells by phenolic antioxidants, azo dyes, and other chemoprotectors: a model system for the study of anticarcinogens.

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