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. 1991 Feb 1;273(Pt 3):711–717. doi: 10.1042/bj2730711

The potency of inducers of NAD(P)H:(quinone-acceptor) oxidoreductase parallels their efficiency as substrates for glutathione transferases. Structural and electronic correlations.

S R Spencer 1, L A Xue 1, E M Klenz 1, P Talalay 1
PMCID: PMC1150218  PMID: 1900000

Abstract

Induction of glutathione transferases (EC. 2.5.1.18), NAD(P)H:(quinone-acceptor) oxidoreductase (EC 1.6.99.2; quinone reductase) and other detoxification enzymes is a major mechanism for protecting cells against the toxicities of electrophiles, including many carcinogens. Although inducers of these two enzymes belong to many different chemical classes, they nevertheless contain (or acquire by metabolism) electrophilic centres that appear to be essential for inclusive activity, and many inducers are Michael reaction acceptors [Talalay, De Long & Prochaska (1988) Proc. Natl. Acad. Sci. U.S.A., 85, 8261-8265]. The inducers therefore share structural and electronic features with glutathione transferase substrates. To define these features more precisely, we examined the inductive potencies (by measuring quinone reductase in murine hepatoma cells) of two types of glutathione transferase substrates: a series of 1-chloro-2-nitrobenzenes bearing para-oriented electron-donating or -withdrawing substituents and a wide variety of other commonly used and structurally unrelated glutathione transferase substrates. We conclude that virtually all glutathione transferase substrates are inducers, and their potencies in the nitrobenzene series correlate linearly with the Hammett sigma or sigma- values of the aromatic substituents, precisely as previously reported for their efficiencies as glutathione transferase substrates. More detailed information on the electronic requirements for inductive activity was obtained with a series of methyl trans-cinnamates bearing electron-withdrawing or -donating substituents on the aromatic ring, and in which the electronic densities at the olefinic and adjacent carbon atoms were measured by 13C n.m.r. Electron-withdrawing meta-substituents markedly enhance inductive potency in parallel with their increased non-enzymic reactivity with GSH. Thus, methyl 3-bromo-, 3-nitro- and 3-chloro-cinnamates are 21, 14 and 8 times more potent inducers than the parent methyl cinnamate. This finding permits the design of more potent inducers, which are important for elucidation of the molecular mechanisms of induction.

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Selected References

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

  1. Benson A. M., Hunkeler M. J., Morrow J. F. Kinetics of glutathione transferase, glutathione transferase messenger RNA, and reduced nicotinamide adenine dinucleotide (phosphate):quinone reductase induction by 2(3)-tert-butyl-4-hydroxyanisole in mice. Cancer Res. 1984 Nov;44(11):5256–5261. [PubMed] [Google Scholar]
  2. Boyland E., Chasseaud L. F. Enzyme-catalysed conjugations of glutathione with unsaturated compounds. Biochem J. 1967 Jul;104(1):95–102. doi: 10.1042/bj1040095. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Chasseaud L. F. The role of glutathione and glutathione S-transferases in the metabolism of chemical carcinogens and other electrophilic agents. Adv Cancer Res. 1979;29:175–274. doi: 10.1016/s0065-230x(08)60848-9. [DOI] [PubMed] [Google Scholar]
  4. De Long M. J., Dolan P., Santamaria A. B., Bueding E. 1,2-Dithiol-3-thione analogs: effects on NAD(P)H:quinone reductase and glutathione levels in murine hepatoma cells. Carcinogenesis. 1986 Jun;7(6):977–980. doi: 10.1093/carcin/7.6.977. [DOI] [PubMed] [Google Scholar]
  5. De Long M. J., Prochaska H. J., Talalay P. 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. Proc Natl Acad Sci U S A. 1986 Feb;83(3):787–791. doi: 10.1073/pnas.83.3.787. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. De Long M. J., Santamaria A. B., Talalay P. Role of cytochrome P1-450 in the induction of NAD(P)H:quinone reductase in a murine hepatoma cell line and its mutants. Carcinogenesis. 1987 Oct;8(10):1549–1553. doi: 10.1093/carcin/8.10.1549. [DOI] [PubMed] [Google Scholar]
  7. Keen J. H., Habig W. H., Jakoby W. B. Mechanism for the several activities of the glutathione S-transferases. J Biol Chem. 1976 Oct 25;251(20):6183–6188. [PubMed] [Google Scholar]
  8. Keen J. H., Habig W. H., Jakoby W. B. Mechanism for the several activities of the glutathione S-transferases. J Biol Chem. 1976 Oct 25;251(20):6183–6188. [PubMed] [Google Scholar]
  9. Mannervik B., Danielson U. H. Glutathione transferases--structure and catalytic activity. CRC Crit Rev Biochem. 1988;23(3):283–337. doi: 10.3109/10409238809088226. [DOI] [PubMed] [Google Scholar]
  10. Morgenstern R., Lundqvist G., Hancock V., DePierre J. W. Studies on the activity and activation of rat liver microsomal glutathione transferase, in particular with a substrate analogue series. J Biol Chem. 1988 May 15;263(14):6671–6675. [PubMed] [Google Scholar]
  11. Pearson W. R., Windle J. J., Morrow J. F., Benson A. M., Talalay P. Increased synthesis of glutathione S-transferases in response to anticarcinogenic antioxidants. Cloning and measurement of messenger RNA. J Biol Chem. 1983 Feb 10;258(3):2052–2062. [PubMed] [Google Scholar]
  12. Prochaska H. J., De Long M. J., Talalay P. On the mechanisms of induction of cancer-protective enzymes: a unifying proposal. Proc Natl Acad Sci U S A. 1985 Dec;82(23):8232–8236. doi: 10.1073/pnas.82.23.8232. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Prochaska H. J., Santamaria A. B. Direct measurement of NAD(P)H:quinone reductase from cells cultured in microtiter wells: a screening assay for anticarcinogenic enzyme inducers. Anal Biochem. 1988 Mar;169(2):328–336. doi: 10.1016/0003-2697(88)90292-8. [DOI] [PubMed] [Google Scholar]
  14. Prochaska H. J., Talalay P. Regulatory mechanisms of monofunctional and bifunctional anticarcinogenic enzyme inducers in murine liver. Cancer Res. 1988 Sep 1;48(17):4776–4782. [PubMed] [Google Scholar]
  15. Talalay P., De Long M. J., Prochaska H. J. Identification of a common chemical signal regulating the induction of enzymes that protect against chemical carcinogenesis. Proc Natl Acad Sci U S A. 1988 Nov;85(21):8261–8265. doi: 10.1073/pnas.85.21.8261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Wattenberg L. W. Chemoprevention of cancer. Cancer Res. 1985 Jan;45(1):1–8. [PubMed] [Google Scholar]

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