Antioxidants and the mutagenicity of benzo(a) pyrene and some derivatives

Calle, Luz M.; Sullivan, Paul D.; Nettleman, Mary D.; Ocasio, Ignacio; Blazyk, John F.; Jollick, J. D.

doi:10.1016/s0006-291x(78)80049-7

Cited by 37 publications

(9 citation statements)

References 16 publications

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“…1 for a review). It reduces the mutagenic activity of benzo [a]pyrene and other promutagens both in vivo (2) and in vitro (3)(4)(5) and protects animals against the acute toxic effects of mutagenic and carcinogenic compounds (6,7). This paper reports large increases in the specific activities of the enzyme NAD(P)H:quinone reductase [NAD(P)H dehydrogenase (quinone); NAD(P)H:(quinone acceptor) oxidoreductase, EC 1.6.99.21 in the cytosols of a number of tissues of albino mice fed a diet containing BHA.…”

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confidence: 99%

“…Addition-of FAD to the assay medium at concentrations of [1][2][3][4][5][6][7][8][9][10] ,MM yielded optimal enzymatic activity and excellent linearity of product formation with time as well as with the concentration of cytosol in the assay system. FMN also enhanced activity but was less effective than FAD.…”

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confidence: 99%

“…These inducers include BHA, 3,5-di-tert-butyl- 4 caused by this hydrocarbon (6). Hemorrhage and necrosis of the adrenal cortex in the rat after administration of 7J,1T2-dimethylbenrz[a]anthracene, which was first described by Huggins and Morii (50), can be prevented by prior treatment with small doses of the same hydrocarbon or with various other aromatic compounds (38,51 (52).…”

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Increase of NAD(P)H:quinone reductase by dietary antioxidants: possible role in protection against carcinogenesis and toxicity.

Benson¹,

Hunkeler²,

Talalay³

1980

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

635

338

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2(3)tert-Butyl4hydroxyanisole (BHA) is one of several widely used antioxidant food additives that protect against chemical carcinogenesis and toxicity. The present report concerns the enhancement of dicoumarolinhibited NAD(P)HL quinone reductase [NAD(P)H dehydrogenase (quinone); NAD(P)H:(quinone acceptor) oxidoreductase, EC 1.6.99.21 activity in mouse tissues in response to dietary administration of BHA. Cytosolic quinone reductase specific activity was increased significantly in 10 of 15 tissues examined from BHA-fed mice. The greatest proportionate increase, to 10 times control levels, was observed in liver. BHA also increased the quinone reductase activities of kidney, lung, and the mucosa of the upper small intestine severalfold. The increases of quinone reductase activities in liver and digestive tissues in response to BHA were comparable to the increases previously observed in glutathione S-transferase (EC 2.5.1.18) and epoxide hydratase (EC 3.3.2.3) activities. Quinones are among the toxic products of oxidative metabolism of aromatic hydrocarbons. NAD(P)H:quinone reductase exhibits broad specificity for structurally diverse hydrophobic quinones an may facilitate the microsomal metabolism of quinones to readily excreted conjugates. The protectie effects of BHA appear to be due, at least in part, to the ability of this antioxidant to increase the activities in rodent tissues of several enzymes involved in the nonoxidative metabolism of a wide variety of xenobiotics.The widely used antioxidant food additive 2(3)-tert-butyl-4-hydroxyanisole (BHA) has a number of interesting and potentially important pharmacological properties. BHA Administration of BHA to mice has little or no effect on numerous other monooxygenase activities of hepatic microsomes (11,15,17), although ring hydroxylation of aniline is markedly enhanced (11). Liver microsomes from BHA-fed mice also produce altered patterns of metabolites from benzo[a]pyrene in vitro. Lam and Wattenberg (18) observed decreased epoxidation and increased formation of 3-hydroxybenzo[a]pyrene relative to controls, and these changes were accompanied by a 50% decrease in the binding of metabolites to DNA (19,20).The NADH-and NADPH-linked quinone oxidoreductase here called quinone reductase has also been designated variously as menadione reductase, DT-diaphorase, NAD(P)H dehydrogenase, and vitamin K reductase (21). Recent studies have shown that rat liver cytosol azoreductase activity for methyl red also reflects the action of quinone reductase (22, 23). Unusual features of this flavoprotein enzyme include: (i) comparable reaction with NADH and NADPH (24-26); (ti) potent and specific inhibition, in competition with reduced nicotinamide nucleotides, by dicoumarol and related vitamin K antagonists (24, 27); (iii) reversible stimulation of activity of the soluble cytosolic quinone reductase by serum albumin, neutral phospholipids, and a number of detergents (24,26,27); and (iv) broad specificity for a variety of hydrophobic quinones, including benzoquinones, na...

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Increase of NAD(P)H:quinone reductase by dietary antioxidants: possible role in protection against carcinogenesis and toxicity.

Benson¹,

Hunkeler²,

Talalay³

1980

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

635

338

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“…Benzo[a]pyrene is included within the EPA34 list and is often used to assess the carcinogenic and mutagenic risk of a contaminated site . However, alkylated benzo[a]pyrene isomers are not included in either the EPA34 list or the risk assessments and, for example, both 6‐methyl benzo[a]pyrene and 10‐methyl benzo[a]pyrene are more mutagenic than benzo[a]pyrene itself . A total of seven potential isomers of benzo[a]pyrene were identified within every sample, although the specific parent PAH isomer could not be determined.…”

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confidence: 99%

Comprehensive database of Manufactured Gas Plant tars. Part A. Database

Gallacher

Thomas²,

Lord

et al. 2017

Rapid Commun Mass Spectrom

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RATIONALECoal tars are a mixture of both organic and inorganic compounds and were produced as a by-product from the manufactured gas and coke making industries. Different manufacturing processes have resulted in the production of distinctly different tar compositions. This study presents a comprehensive database of compounds produced using two-dimensional gas chromatography combined with time-of-flight mass spectrometry (GCxGC/TOFMS) analysing 16 tar samples produced by 5 distinct production processes.

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“…When added to commercial diets, it effectively inhibited neoplasia at several sites induced by a variety of carcinogens (Wattenberg, I 972a, b;1973). BHA was also found to lower the mutagenicity of BaP and other promutagens both in vivo (Batzinger et al, 1978) and in vitro (Rahimtula et al, 1977;Calle et al, 1978;McKee & Tometsko, 1979). Dietary administration of BHA to female mice has been shown to increase several fold the specific activities of the Phase II detoxication enzymes, glutathione S-transferases and epoxide hydratase, in the liver and other tissues (Benson et al, 1978a, b;Cha et al, 1978).…”

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confidence: 99%

Effects of dietary and in vitro 2(3)-t-butyl-4-hydroxy-anisole and other phenols on hepatic enzyme activities in mice

Rahimtula¹,

Jernström²,

Dock³

et al. 1982

Br J Cancer

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Summary.-Six phenols [2(3)-t-butyl-4-hydroxyanisole (BHA), 2-t-butylphenol, 4-methoxyphenol, 4-methylmercaptophenol, t-butylhydroquinone and 2,6-di-tbutylphenol] previously shown to be inhibitors of benzo(a)pyrene-induced neoplasia, were examined for their ability to induce in vivo changes in hepatic mono -oxygenase and detoxication enzyme activities, and to act as mono-oxygenase inhibitors when added in vitro. (1) Generally it was found that cytochrome P450 levels were depressed, only 2,6-di-t-butylphenol caused a 2-fold induction (2) Mono-oxygenase activities were significantly altered; BHA and 2,6-di-t-butylphenol caused microsomes to show substantial increases in aniline hydroxylase and peroxidase activities. These microsomes, along with 4-methoxyphenol microsomes, also showed a substantial reduction in DNA binding of benzo(a)pyrene (BaP) metabolites relative to metabolism. (3) Detoxication enzymes glutathione S-transferases and epoxide hydratase were readily induced, the order of effectiveness being: BHA -2,6-di-t-butylphenol> 4-methoxyphenol > 2 -t -butylphenol -t-butylhydroquinone (4-methylmercaptophenol failed to induce). (4) In vitro ability to inhibit BaP metabolism and DNA-binding ability was: 2,6-di-t-butylphenol , BHA -2-t-butylphenol> t-butylhydroquinone> 4-methylmercaptophenol1>4-methoxyphenol. (5) Ability in vitro to discharge the activated oxygen complex of cytochrome P450 was: 2,6-di-t-butylphenol-,2-t-butylphenol > BHA > t-butlyhydroquinone > 4-methylmercaptophenol > 4-methoxyphenol. The results are consistent with the theory that inhibition of neoplasia is related to inducibility of detoxication enzymes, though alterations in cytochrome P450 could play a significant role in some cases.

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Antioxidants and the mutagenicity of benzo(a) pyrene and some derivatives

Cited by 37 publications

References 16 publications

Increase of NAD(P)H:quinone reductase by dietary antioxidants: possible role in protection against carcinogenesis and toxicity.

Increase of NAD(P)H:quinone reductase by dietary antioxidants: possible role in protection against carcinogenesis and toxicity.

Comprehensive database of Manufactured Gas Plant tars. Part A. Database

Effects of dietary and in vitro 2(3)-t-butyl-4-hydroxy-anisole and other phenols on hepatic enzyme activities in mice

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