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. 1982 Jun;45(6):935–944. doi: 10.1038/bjc.1982.146

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

A D Rahimtula, B Jernström, L Dock, P Moldeus
PMCID: PMC2011042  PMID: 7093125

Abstract

Six phenols [2(3)-t-butyl-4-hydroxyanisole (BHA), 2-t-butylphenol, 4-methoxyphenol, 4-methylmercaptophenol, t-butylhydroquinone and 2,6-di-t-butylphenol] 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 approximately 2,6-di-t-butylphenol greater than 4-methoxyphenol greater than 2-t-butylphenol approximately 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 greater than or equal to BHA approximately 2-t-butylphenol greater than t-butylhydroquinone greater than 4-methylmercaptophenol greater than 4-methoxyphenol. (5) Ability in vitro to discharge the activated oxygen complex of cytochrome P450 was: 2,6-di-t-butylphenol approximately 2-t-butylphenol greater than BHA greater t-butylhydroquinone greater than 4-methylmercaptophenol greater than 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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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Batzinger R. P., Ou S. Y., Bueding E. Antimutagenic effects of 2(3)-tert-butyl-4-hydroxyanisole and of antimicrobial agents. Cancer Res. 1978 Dec;38(12):4478–4485. [PubMed] [Google Scholar]
  2. Benson A. M., Cha Y. N., Bueding E., Heine H. S., 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] [Google Scholar]
  3. Bock K. W., White I. N. UDP-glucuronyltransferase in perfused rat liver and in microsomes: influence of phenobarbital and 3-methylcholanthrene. Eur J Biochem. 1974 Aug 1;46(3):451–459. [PubMed] [Google Scholar]
  4. Calle L. M., Sullivan P. D., Nettleman M. D., Ocasio I. J., 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. doi: 10.1016/s0006-291x(78)80049-7. [DOI] [PubMed] [Google Scholar]
  5. Cha Y. N., 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. doi: 10.1016/0006-2952(79)90645-2. [DOI] [PubMed] [Google Scholar]
  6. Cha Y. N., 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] [Google Scholar]
  7. Dansette P. M., DuBois G. C., Jerina D. M. Continous fluorometric assay of epoxide hydrase activity. Anal Biochem. 1979 Sep 1;97(2):340–345. doi: 10.1016/0003-2697(79)90083-6. [DOI] [PubMed] [Google Scholar]
  8. Friedberg T., Bentley P., Stasiecki P., Glatt H. R., Raphael D., Oesch F. The identification, solubilization, and characterization of microsome-associated glutathione S-transferases. J Biol Chem. 1979 Dec 10;254(23):12028–12033. [PubMed] [Google Scholar]
  9. Fujita T., Mannering G. J. Electron transport components of hepatic microsomes. Solubilization, resolution, and recombination to reconstitute aniline hydroxylase activity. J Biol Chem. 1973 Dec 10;248(23):8150–8156. [PubMed] [Google Scholar]
  10. GEORGE P., IRVINE D. H. The reaction between metmyoglobin and alkyl hydro-peroxides. Biochem J. 1953 Sep;55(2):230–236. doi: 10.1042/bj0550230. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Guenthner T. M., Jernström B., Orrenius S. Effects of different cell constituents on metabolic activation and binding of benzo(a)pyrene to purified and nuclear DNA. Biochem Biophys Res Commun. 1979 Dec 14;91(3):842–848. doi: 10.1016/0006-291x(79)91956-9. [DOI] [PubMed] [Google Scholar]
  12. Guenthner T. M., Oesch F. The effects of modulation of microsomal epoxide hydrolase activity on microsome-catalyzed activation of benzo[alpha]pyrene and its covalent binding to DNA. Cancer Lett. 1981 Jan;11(3):175–183. doi: 10.1016/0304-3835(81)90105-1. [DOI] [PubMed] [Google Scholar]
  13. Hrycay E. C., O'Brien P. J. Cytochrome P-450 as a microsomal peroxidase in steroid hydroperoxide reduction. Arch Biochem Biophys. 1972 Dec;153(2):480–494. doi: 10.1016/0003-9861(72)90366-9. [DOI] [PubMed] [Google Scholar]
  14. Kahl R., Deckers-Schmelzle B., Klaus E. Ethoxyquin feeding to rats increases liver microsome-catalyzed formation of benzo(a)pyrene diol epoxide--DNA adduct. Biochem Biophys Res Commun. 1978 Dec 14;85(3):938–945. doi: 10.1016/0006-291x(78)90634-4. [DOI] [PubMed] [Google Scholar]
  15. Lam L. K., Fladmoe A. V., Hochalter J. B., Wattenberg L. W. Short time interval effects of butylated hydroxyanisole on the metabolism of benzo(a)pyrene. Cancer Res. 1980 Aug;40(8 Pt 1):2824–2828. [PubMed] [Google Scholar]
  16. Lam L. K., Wattenberg L. W. 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. doi: 10.1093/jnci/58.2.413. [DOI] [PubMed] [Google Scholar]
  17. Morgenstern R., Meijer J., Depierre J. W., Ernster L. Characterization of rat-liver microsomal glutathione S-transferase activity. Eur J Biochem. 1980 Feb;104(1):167–174. doi: 10.1111/j.1432-1033.1980.tb04412.x. [DOI] [PubMed] [Google Scholar]
  18. NASH T. The colorimetric estimation of formaldehyde by means of the Hantzsch reaction. Biochem J. 1953 Oct;55(3):416–421. doi: 10.1042/bj0550416. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Nebert D. W., Gelboin H. V. Substrate-inducible microsomal aryl hydroxylase in mammalian cell culture. I. Assay and properties of induced enzyme. J Biol Chem. 1968 Dec 10;243(23):6242–6249. [PubMed] [Google Scholar]
  20. OMURA T., SATO R. THE CARBON MONOXIDE-BINDING PIGMENT OF LIVER MICROSOMES. I. EVIDENCE FOR ITS HEMOPROTEIN NATURE. J Biol Chem. 1964 Jul;239:2370–2378. [PubMed] [Google Scholar]
  21. Rahimtula A. D., O'Brien P. J., Hrycay E. G., Peterson J. A., Estabrook R. W. Possible higher valence states of cytochrome P-450 during oxidative reactions. Biochem Biophys Res Commun. 1974 Sep 23;60(2):695–702. doi: 10.1016/0006-291x(74)90296-4. [DOI] [PubMed] [Google Scholar]
  22. Rahimtula A. D., O'Brien P. J. Hydroperoxide catalyzed liver microsomal aromatic hydroxylation reactions involving cytochrome P-450. Biochem Biophys Res Commun. 1974 Sep 9;60(1):440–447. doi: 10.1016/0006-291x(74)90223-x. [DOI] [PubMed] [Google Scholar]
  23. Rahimtula A. D., O'Brien P. J. Hydroperoxide dependent O-dealkylation reactions catalyzed by liver microsomal cytochrome P450. Biochem Biophys Res Commun. 1975 Jan 20;62(2):268–275. doi: 10.1016/s0006-291x(75)80133-1. [DOI] [PubMed] [Google Scholar]
  24. Rahimtula A. D., Zachariah P. K., O'Brien P. J. Differential effects of antioxidants, steroids and other compounds on benzo(a)pyrene 3-hydroxylase activity in various tissues of rat. Br J Cancer. 1979 Jul;40(1):105–112. doi: 10.1038/bjc.1979.146. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Rahimtula A. D., Zachariah P. K., O'Brien P. J. The effects of antioxidants on the metabolism and mutagenicity of benzo[a]pyrene in vitro. Biochem J. 1977 May 15;164(2):473–475. doi: 10.1042/bj1640473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Sparnins V. L., Wattenberg L. W. Enhancement of glutathione S-transferase activity of the mouse forestomach by inhibitors of Benzo[a]pyrene-induced neoplasia of the forestomach. J Natl Cancer Inst. 1981 Apr;66(4):769–771. [PubMed] [Google Scholar]
  27. Speier J. L., Wattenberg L. W. Alterations in microsomal metabolism of benzo[a]pyrene in mice fed butylated hydroxyanisole. J Natl Cancer Inst. 1975 Aug;55(2):469–472. [PubMed] [Google Scholar]
  28. Van Cantfort J., De Graeve J., Gielen J. E. Radioactive assay for aryl hydrocarbon hydroxylase. Improved method and biological importance. Biochem Biophys Res Commun. 1977 Nov 21;79(2):505–512. doi: 10.1016/0006-291x(77)90186-3. [DOI] [PubMed] [Google Scholar]
  29. Wattenberg L. W., Coccia J. B., Lam L. K. Inhibitory effects of phenolic compounds on benzo(a)pyrene-induced neoplasia. Cancer Res. 1980 Aug;40(8 Pt 1):2820–2823. [PubMed] [Google Scholar]
  30. Wattenberg L. W. 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] [Google Scholar]
  31. Yamazaki I., Yokota K. Oxidation states of peroxidase. Mol Cell Biochem. 1973 Nov 15;2(1):39–52. doi: 10.1007/BF01738677. [DOI] [PubMed] [Google Scholar]
  32. Yang C. S., Strickhart F. S., Woo G. K. Inhibition of the mono-oxygenase system by butylated hydroxyanisole and butylated hydroxytoluene. Life Sci. 1974 Oct 15;15(8):1497–1505. doi: 10.1016/0024-3205(74)90124-6. [DOI] [PubMed] [Google Scholar]

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