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Titolo:
Role of phase 2 enzyme induction in chemoprotection by dithiolethiones
Autore:
Kwak, MK; Egner, PA; Dolan, PM; Ramos-Gomez, M; Groopman, JD; Itoh, K; Yamamoto, M; Kensler, TW;
Indirizzi:
Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD 21205 USA Johns Hopkins Univ Baltimore MD USA 21205 th Sci, Baltimore, MD 21205 USA Univ Tsukuba, Ctr TARA, Tsukuba, Ibaraki 3058577, Japan Univ Tsukuba Tsukuba Ibaraki Japan 3058577 sukuba, Ibaraki 3058577, Japan
Titolo Testata:
MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS
, volume: 480, anno: 2001,
pagine: 305 - 315
SICI:
1386-1964(20010901)480:<305:ROP2EI>2.0.ZU;2-F
Fonte:
ISI
Lingua:
ENG
Soggetto:
REPUBLIC-OF-CHINA; ANTIOXIDANT RESPONSE ELEMENT; GLUTATHIONE S-TRANSFERASES; OLTIPRAZ CHEMOPREVENTION TRIAL; YA-SUBUNIT GENE; 5-(2-PYRAZINYL)-4-METHYL-1,2-DITHIOL-3-THIONE OLTIPRAZ; INDUCIBLE EXPRESSION; DETOXIFY CARCINOGENS; AFLATOXIN B-1; F344 RATS;
Keywords:
oltipraz; 1,2-dithiole-3-thiones chemoprotection; Nrf2; glutathione S-transferases; aflatoxin;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
62
Recensione:
Indirizzi per estratti:
Indirizzo: Kensler, TW Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, 615 Wolfe St, Baltimore, MD 21205 USA Johns Hopkins Univ 615 Wolfe St Baltimore MD USA 21205 205 USA
Citazione:
M.K. Kwak et al., "Role of phase 2 enzyme induction in chemoprotection by dithiolethiones", MUT RES-F M, 480, 2001, pp. 305-315

Abstract

One of the major mechanisms of protection against carcinogenesis, muta(g)enesis, and other forms of toxicity mediated by carcinogens is the inductionof enzymes involved in their metabolism, particularly phase 2 enzymes suchas 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 ledto 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 B-1 (AFB(1))-induced hepatocarcinogenesis by oltipraz indicates that increased expressionof phase 2 genes is of central importance, although inhibition of phase 1 activation of AFB(1) can also contribute to protection. Exposure of rodentsto 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 involvedin 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 testthe 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 inter-mediate endpoints. Towards this end, aplacebo-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 of500 mg oltipraz once a week led to a significant reduction in the excretion of the primary oxidative metabolite of AFB(1), AFM(1), 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 besustained for extended periods of time in this high-risk population. (C) 2001 Elsevier Science B.V. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 06/04/20 alle ore 06:04:07