Role of phase 2 enzyme induction in chemoprotection by dithiolethiones

Mi Kyoung Kwak, Patricia Egner, Patrick M. Dolan, Minerva Ramos-Gomez, John Davis Groopman, Ken Itoh, Masayuki Yamamoto, Thomas W Kensler

Research output: Contribution to journalArticle

Abstract

One of the major mechanisms of protection against carcinogenesis, mutagenesis, and other forms of toxicity mediated by carcinogens is the induction of enzymes involved in their metabolism, particularly phase 2 enzymes such as glutathione S-transferases (GSTs), UDP-glucuronosyl transferases, and quinone reductases. Animal studies indicate that induction of phase 2 enzymes is a sufficient condition for obtaining chemoprevention and can be achieved by administering any of a diverse array of naturally-occurring and synthetic chemopreventive agents. Indeed, monitoring of enzyme induction has led to the recognition or isolation of novel, potent chemopreventive agents such as 1,2-dithiole-3-thiones, terpenoids and the isothiocyanate sulforaphane. For example, oltipraz, a substituted 1,2-dithiole-3-thione originally developed as an antischistosomal agent, possesses chemopreventive activity against different classes of carcinogens targeting multiple organs. Mechanistic studies in rodent models for chemoprevention of aflatoxin B1 (AFB1)-induced hepatocarcinogenesis by oltipraz indicates that increased expression of phase 2 genes is of central importance, although inhibition of phase 1 activation of AFB1 can also contribute to protection. Exposure of rodents to 1,2-dithiole-3-thiones triggers nuclear accumulation of the transcription factor Nrf2 and its enhanced binding to the "antioxidant response element" (ARE), leading to transcriptional activation of a score of genes involved in carcinogen detoxication and attenuation of oxidative stress. Nrf2-deficient mice fail to induce many of these genes in response to dithiolethiones; moreover, basal expression of these genes is typically repressed. To test the hypothesis that enzyme induction is a useful strategy for chemoprevention in humans, three key elements are necessary: a candidate agent, an at-risk population and modulatable intermediate endpoints. Towards this end, a placebo-controlled, double blind clinical trial of oltipraz was conducted in residents of Qidong, PR China who are exposed to dietary aflatoxins and who are at high risk for the development of liver cancer. Oltipraz significantly enhanced excretion of a phase 2 product, aflatoxin-mercapturic acid, a derivative of the aflatoxin-glutathione conjugate, in the urine of study participants administered 125 mg oltipraz by mouth daily. Administration of 500 mg oltipraz once a week led to a significant reduction in the excretion of the primary oxidative metabolite of AFB1, AFM1, when measured shortly after drug administration. While this study highlighted the general feasibility of inducing phase 2 enzymes in humans, a longer term intervention is addressing whether protective alterations in aflatoxin metabolism can be sustained for extended periods of time in this high-risk population.

Original languageEnglish (US)
Pages (from-to)305-315
Number of pages11
JournalMutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
Volume480-481
StatePublished - Sep 1 2001

Fingerprint

Enzyme Induction
Aflatoxins
Aflatoxin B1
Chemoprevention
Carcinogens
Quinone Reductases
Schistosomicides
Rodentia
Enzymes
Antioxidant Response Elements
Genes
Uridine Diphosphate
Terpenes
Acetylcysteine
Liver Neoplasms
Transferases
Glutathione Transferase
Mutagenesis
Transcriptional Activation
Glutathione

Keywords

  • 1,2-Dithiole-3-thiones
  • Aflatoxin
  • Chemoprotection
  • Glutathione S-transferases
  • Nrf2
  • Oltipraz

ASJC Scopus subject areas

  • Health, Toxicology and Mutagenesis
  • Molecular Biology

Cite this

Role of phase 2 enzyme induction in chemoprotection by dithiolethiones. / Kwak, Mi Kyoung; Egner, Patricia; Dolan, Patrick M.; Ramos-Gomez, Minerva; Groopman, John Davis; Itoh, Ken; Yamamoto, Masayuki; Kensler, Thomas W.

In: Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, Vol. 480-481, 01.09.2001, p. 305-315.

Research output: Contribution to journalArticle

Kwak, Mi Kyoung ; Egner, Patricia ; Dolan, Patrick M. ; Ramos-Gomez, Minerva ; Groopman, John Davis ; Itoh, Ken ; Yamamoto, Masayuki ; Kensler, Thomas W. / Role of phase 2 enzyme induction in chemoprotection by dithiolethiones. In: Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis. 2001 ; Vol. 480-481. pp. 305-315.
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