Regulation of enzymes that detoxify the electrophilic forms of chemical carcinogens.

Paul Talalay, H. J. Prochaska, S. R. Spencer

Research output: Contribution to journalArticle

Abstract

Most chemical carcinogens require activation to reactive electrophilic forms by Phase 1 enzymes (cytochromes P-450) in order to exert their toxic and neoplastic effects. The resultant electrophiles are susceptible to metabolic conjugation and other types of detoxications by Phase 2 enzymes (glutathione transferases, NAD(P)H: quinone reductase, glucuronosyltransferases). The balance between Phase 1 and Phase 2 enzymes is an important determinant of whether exposure to carcinogens will result in toxicity and neoplasia. Measurements of the activity of quinone reductase (QR) provide an efficient method for studying the potency and mechanism of Phase 2 enzyme induction. QR can be measured easily in murine hepatoma cells (Hepa lclc7) grown in microtiter plate wells, and the inductive response of these cells closely parallels the behavior of rodent tissues in vivo. Some inducers (such as large planar aromatics) are bifunctional; they induce both Phase 1 and Phase 2 enzymes and require binding to the Ah receptor and enhanced transcription of the cytochrome P1-450 system. Other inducers (e.g., phenolic antioxidants, 1, 2-dithiole-3-thiones, coumarins, thiocarbamates) are monofunctional and are independent of Ah receptor function. Monofunctional enzyme induction protects against carcinogens. The induction of Phase 2 enzymes by monofunctional inducers depends on the presence, or acquisition by metabolism, of electrophilic centers, and many of these inducers are Michael reaction acceptors. Our search for chemoprotective enzyme inducers for potential use as chemoprotectors in man is currently focused on fumarate derivatives, as well as on the identification of other monofunctional inducers in extracts of vegetables.

Original languageEnglish (US)
Pages (from-to)177-187
Number of pages11
JournalPrincess Takamatsu symposia
Volume21
StatePublished - 1990

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Carcinogens
NAD(P)H Dehydrogenase (Quinone)
Enzymes
Enzyme Induction
Thiocarbamates
Coumarins
Glucuronosyltransferase
Fumarates
Poisons
Cytochromes
Glutathione Transferase
Vegetables
NAD
Cytochrome P-450 Enzyme System
Hepatocellular Carcinoma
Rodentia
Antioxidants
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Regulation of enzymes that detoxify the electrophilic forms of chemical carcinogens. / Talalay, Paul; Prochaska, H. J.; Spencer, S. R.

In: Princess Takamatsu symposia, Vol. 21, 1990, p. 177-187.

Research output: Contribution to journalArticle

Talalay, Paul ; Prochaska, H. J. ; Spencer, S. R. / Regulation of enzymes that detoxify the electrophilic forms of chemical carcinogens. In: Princess Takamatsu symposia. 1990 ; Vol. 21. pp. 177-187.
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