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Proc Natl Acad Sci U S A. Sep 1980; 77(9): 5216–5220.
PMCID: PMC350028

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

Abstract

2(3)-tert-Butyl-4-hydroxyanisole (BHA) is one of several widely used antioxidant food additives that protect against chemical carcinogenesis and toxicity. The present report concerns the enhancement of dicoumarol-inhibited NAD(P)H:quinone reductase [NAD(P)H dehydrogenase (quinone); NAD(P)H:(quinone acceptor) oxidoreductase, EC 1.6.99.2] 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 and may facilitate the microsomal metabolism of quinones to readily excreted conjugates. The protective 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.

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  • Wattenberg LW. Inhibitors of chemical carcinogenesis. Adv Cancer Res. 1978;26:197–226. [PubMed]
  • Batzinger RP, Ou SY, Bueding E. Antimutagenic effects of 2(3)-tert-butyl-4-hydroxyanisole and of antimicrobial agents. Cancer Res. 1978 Dec;38(12):4478–4485. [PubMed]
  • Rahimtula AD, Zachariah PK, O'Brien PJ. The effects of antioxidants on the metabolism and mutagenicity of benzo[a]pyrene in vitro. Biochem J. 1977 May 15;164(2):473–475. [PMC free article] [PubMed]
  • Calle LM, Sullivan PD, Nettleman MD, Ocasio IJ, Blazyk J, Jollick J. Antioxidants and the mutagenicity of benzo(a) pyrene and some derivatives. Biochem Biophys Res Commun. 1978 Nov 14;85(1):351–356. [PubMed]
  • McKee RH, Tometsko AM. Inhibition of promutagen activation by the antioxidants butylated hydroxyanisole and butylated hydroxytoluene. J Natl Cancer Inst. 1979 Aug;63(2):473–477. [PubMed]
  • Wattenberg LW. Inhibition of carcinogenic and toxic effects of polycyclic hydrocarbons by phenolic antioxidants and ethoxyquin. J Natl Cancer Inst. 1972 May;48(5):1425–1430. [PubMed]
  • Cumming RB, Walton MF. Modification of the acute toxicity of mutagenic and carcinogenic chemicals in the mouse by prefeeding with antioxidants. Food Cosmet Toxicol. 1973 Aug;11(4):547–553. [PubMed]
  • Benson AM, Batzinger RP, Ou SY, Bueding E, Cha YN, Talalay P. Elevation of hepatic glutathione S-transferase activities and protection against mutagenic metabolites of benzo(a)pyrene by dietary antioxidants. Cancer Res. 1978 Dec;38(12):4486–4495. [PubMed]
  • Benson AM, Cha YN, Bueding E, Heine HS, Talalay P. Elevation of extrahepatic glutathione S-transferase and epoxide hydratase activities by 2(3)-tert-butyl-4-hydroxyanisole. Cancer Res. 1979 Aug;39(8):2971–2977. [PubMed]
  • Cha YN, Martz F, Bueding E. Enhancement of liver microsome epoxide hydratase activity in rodents by treatment with 2(3)-tert-butyl-4-hydroxyanisole. Cancer Res. 1978 Dec;38(12):4496–4498. [PubMed]
  • Cha YN, Bueding E. Effects of 2(3)-tert-butyl-4-hydroxyanisole administration on the activities of several hepatic microsomal and cytoplasmic enzymes in mice. Biochem Pharmacol. 1979 Jun 15;28(12):1917–1921. [PubMed]
  • Talalay P, Batzinger RP, Benson AM, Bueding E, Cha YN. Biochemical studies on the mechanisms by which dietary antioxidants suppress mutagenic activity. Adv Enzyme Regul. 1978;17:23–36. [PubMed]
  • Bueding E, Batzinger RP, Cha YN, Talalay P, Molineaux CJ. Protection from mutagenic effects of antischistosomal and other drugs. Pharmacol Rev. 1978 Dec;30(4):547–554. [PubMed]
  • Kahl R, Wulff U. Induction of rat hepatic epoxide hydratase by dietary antioxidants. Toxicol Appl Pharmacol. 1979 Feb;47(2):217–227. [PubMed]
  • Gilbert D, Martin AD, Gangolli SD, Abraham R, Goldberg L. The effect of substituted phenols on liver weights and liver enzymes in the rat: structure-activity relationships. Food Cosmet Toxicol. 1969 Nov;7(6):603–619. [PubMed]
  • Lam LK, Wattenberg LW. Effects of butylated hydroxyanisole on the metabolism of benzo[a]pyrene by mouse liver microsomes. J Natl Cancer Inst. 1977 Feb;58(2):413–417. [PubMed]
  • Speier JL, Wattenberg LW. Alterations in microsomal metabolism of benzo[a]pyrene in mice fed butylated hydroxyanisole. J Natl Cancer Inst. 1975 Aug;55(2):469–472. [PubMed]
  • Speier JL, Lam LK, Wattenberg LW. Effects of administration to mice of butylated hydroxyanisole by oral intubation on benzo[a]pyrene-induced pulmonary adenoma formation and metabolism of benzo[a]pyrene. J Natl Cancer Inst. 1978 Mar;60(3):605–609. [PubMed]
  • Huang MT, Miwa GT, Lu AY. Rat liver cytosolic azoreductase. Purification and characterization. J Biol Chem. 1979 May 25;254(10):3930–3934. [PubMed]
  • Huang MT, Miwa GT, Cronheim N, Lu AY. Rat liver cytosolic azoreductase. Electron transport properties and the mechanism of dicumarol inhibition of the purified enzyme. J Biol Chem. 1979 Nov 25;254(22):11223–11227. [PubMed]
  • ERNSTER L, DANIELSON L, LJUNGGREN M. DT diaphorase. I. Purification from the soluble fraction of rat-liver cytoplasm, and properties. Biochim Biophys Acta. 1962 Apr 9;58:171–188. [PubMed]
  • MAERKI F, MARTIUS C. [Vitamin K reductase, preparation and properties]. Biochem Z. 1960;333:111–135. [PubMed]
  • Hollander PM, Ernster L. Studies on the reaction mechanism of DT diaphorase. Action of dead-end inhibitors and effects of phospholipids. Arch Biochem Biophys. 1975 Aug;169(2):560–567. [PubMed]
  • WOSILAIT WD. The reduction of vitamin K1 by an enzyme from dog liver. J Biol Chem. 1960 Apr;235:1196–1201. [PubMed]
  • Stenflo J, Suttie JW. Vitamin K-dependent formation of gamma-carboxyglutamic acid. Annu Rev Biochem. 1977;46:157–172. [PubMed]
  • Wallin R, Gebhardt O, Prydz H. NAD(P)H dehydrogenase and its role in the vitamin K (2-methyl-3-phytyl-1,4-naphthaquinone)-dependent carboxylation reaction. Biochem J. 1978 Jan 1;169(1):95–101. [PMC free article] [PubMed]
  • Takahashi O, Hiraga K. The relationship between hemorrhage induced by butylated hydroxytoluene and its antioxidant properties or structural characteristics. Toxicol Appl Pharmacol. 1978 Dec;46(3):811–814. [PubMed]
  • Suzuki H, Nakao T, Hiraga K. Vitamin K deficiency in male rats fed diets containing butylated hydroxytoluene (BHT). Toxicol Appl Pharmacol. 1979 Sep 15;50(2):261–266. [PubMed]
  • Hosoda S, Nakamura W, Hayashi K. Properties and reaction mechanism of DT diaphorase from rat liver. J Biol Chem. 1974 Oct 25;249(20):6416–6423. [PubMed]
  • Rase B, Bartfai T, Ernster L. Purification of DT-diaphorase by affinity chromatography. Occurrence of two subunits and nonlinear Dixon and Scatchard plots of the inhibition by anticoagulants. Arch Biochem Biophys. 1976 Feb;172(2):380–386. [PubMed]
  • WILLIAMS-ASHMAN HG, HUGGINS C. Oxydation of reduced pyridine nucleotides in mammary gland and adipose tissue following treatment with polynuclear hydrocarbons. Med Exp Int J Exp Med. 1961;4:223–226. [PubMed]
  • HUGGINS C, FUKUNISHI R. INDUCED PROTECTION OF ADRENAL CORTEX AGAINST 7,12-DIMETHYLBENZ(ALPHA)ANTHRACENE. INFLUENCE OF ETHIONINE. INDUCTION OF MENADIONE REDUCTASE. INCORPORATION OF THYMIDINE-H3. J Exp Med. 1964 Jan 1;119:923–942. [PMC free article] [PubMed]
  • HUGGINS C, PATAKI J. AROMATIC AZO DERIVATIVES PREVENTING MAMMARY CANCER AND ADRENAL INJURY FROM 7,12-DIMETHYLBENZ(A)ANTHRACENE. Proc Natl Acad Sci U S A. 1965 Apr;53:791–796. [PMC free article] [PubMed]
  • Lind C, Ernster L. A possible relationship between DT diaphorase and the aryl hydrocarbon hydroxylase system. Biochem Biophys Res Commun. 1974 Jan 23;56(2):392–400. [PubMed]
  • Beatty P, Neal RA. Induction of DT-diaphorase by 2,3,7,8-tetrachlorodibenzo-p-dioxin (ICDD). Biochem Biophys Res Commun. 1976 Jan 12;68(1):197–204. [PubMed]
  • Schor NA, Boh E, Burke VT. Carcinogens and dicumarol: opposite effects on rat liver NAD(P)H dehydrogenation. Enzyme. 1978;23(4):217–224. [PubMed]
  • Hommes FA, Everts RS, Havinga H. The development of DT-diaphorase in rat liver and its induction by benzo(a)pyrene. Biol Neonate. 1978;34(5-6):248–252. [PubMed]
  • Huang MT, Miwa GT, Lu AY. Induction of rat liver cytosol methyl red azo-reductase by 3-methylcholanthrene assayed by a sensitive fluorometric method. Biochem Biophys Res Commun. 1978 Aug 29;83(4):1253–1259. [PubMed]
  • Huggins CB, Ueda N, Russo A. Azo dyes prevent hydrocarbon-induced leukemia in the rat. Proc Natl Acad Sci U S A. 1978 Sep;75(9):4524–4527. [PMC free article] [PubMed]
  • Haugen DA, Coon MJ. Induction of multiple forms of mouse liver cytochrome P-450. Evidence for genetically controlled de novo protein synthesis in response to treatment with beta-naphthoflavone or phenobarbital. J Biol Chem. 1976 Mar 25;251(6):1817–1827. [PubMed]
  • Kumaki K, Jensen NM, Shire JG, Nebert DW. Genetic differences in induction of cytosol reduced-NAD(P):menadione oxidoreductase and microsomal aryl hydrocarbon hydroxylase in the mouse. J Biol Chem. 1977 Jan 10;252(1):157–165. [PubMed]
  • LOWRY OH, ROSEBROUGH NJ, FARR AL, RANDALL RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed]
  • HUGGINS C, MORII S. Selective adrenal necrosis and apoplexy induced by 7, 12-dimethylbenz(a)anthracene. J Exp Med. 1961 Nov 1;114:741–760. [PMC free article] [PubMed]
  • DAO TL, TANAKA Y. INHIBITORY EFFECT OF POLYNUCLEAR HYDROCARBONS AND AMPHENONE ANALOGS ON INDUCTION OF ACUTE ADRENAL NECROSIS BY 7,12-DIMETHYLBENZ(ALPHA)ANTHRACENE. Cancer Res. 1963 Sep;23:1148–1152. [PubMed]
  • DiGiovanni J, Berry DL, Juchau MR, Slaga TJ. 2,3,7,8-Tetrachlorodibenzo-P-dioxin: potent anticarcinogenic activity in CD-1 mice. Biochem Biophys Res Commun. 1979 Feb 14;86(3):577–584. [PubMed]
  • Horning EC, Thenot JP, Helton ED. Toxic agents resulting from the oxidative metabolism of steroid hormones and drugs. J Toxicol Environ Health. 1978 Mar-May;4(2-3):341–361. [PubMed]
  • Wislocki PG, Wood AW, Chang RL, Levin W, Yagi H, Hernandez O, Dansette PM, Herina DM, Conney AH. Mutagenicity and cytotoxicity of benzo(a)pyrene arene oxides, phenols, quinones, and dihydrodiols in bacterial and mammalian cells. Cancer Res. 1976 Sep;36(9 PT1):3350–3357. [PubMed]
  • Pelkonen O, Boobis AR, Yagi H, Jerina DM, Nebert DW. Tentative identification of benzo[a]pyrene metabolite-nucleoside complexes produced in vitro by mouse liver microsomes. Mol Pharmacol. 1978 Mar;14(2):306–322. [PubMed]
  • Bachur NR, Gordon SL, Gee MV, Kon H. NADPH cytochrome P-450 reductase activation of quinone anticancer agents to free radicals. Proc Natl Acad Sci U S A. 1979 Feb;76(2):954–957. [PMC free article] [PubMed]
  • Lorentzen RJ, Lesko SA, McDonald K, Ts'o PO. Toxicity of metabolic benzo(a)pyrenediones to cultured cells and the dependence upon molecular oxygen. Cancer Res. 1979 Aug;39(8):3194–3198. [PubMed]
  • Capdevila J, Estabrook RW, Prough RA. The existence of a benzo(a)pyrene-3,6-quinone reductase in rat liver microsomal fractions. Biochem Biophys Res Commun. 1978 Aug 29;83(4):1291–1298. [PubMed]
  • Lind C, Vadi H, Ernster L. Metabolism of benzo(a)pyrene-3,6-quinone and 3-hydroxybenzo(a)pyrene in liver microsomes from 3-methylcholanthrene-treated rats. A possible role of DT-diaphorase in the formation of glucuronyl conjugates. Arch Biochem Biophys. 1978 Sep;190(1):97–108. [PubMed]
  • Schor NA, Morris HP. The activity of the D-T diaphorase in experimental hepatomas. Cancer Biochem Biophys. 1977;2(1):5–9. [PubMed]
  • Schor NA. The use of the D-T diaphorase for the detection of foci of early neoplastic transformation in rat liver. Cancer Lett. 1978 Sep;5(3):167–171. [PubMed]
  • Levin W, Lu AY, Thomas PE, Ryan D, Kizer DE, Griffin MJ. Identification of epoxide hydrase as the preneoplastic antigen in rat liver hyperplastic nodules. Proc Natl Acad Sci U S A. 1978 Jul;75(7):3240–3243. [PMC free article] [PubMed]

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