Role of phase 2 enzyme induction in chemoprotection by dithiolethiones

One of the major mechanisms of protection against carcinogenesis, muta(g)en esis, 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 qu inone reductases. Animal studies indicate that induction of phase 2 enzymes is a sufficient condition for obtaining chemoprevention and can be achieve d by administering any of a diverse array of naturally-occurring and synthe tic chemopreventive agents. Indeed, monitoring of enzyme induction has led to the recognition or isolation of novel, potent chemopreventive agents suc h as 1,2-dithiole-3-thiones, terpenoids and the isothiocyanate sulforaphane . For example, oltipraz. a substituted 1,2-dithiole-3-thione originally dev eloped as an antischistosomal agent, possesses chemopreventive activity aga inst different classes of carcinogens targeting multiple organs. Mechanisti c studies in rodent models for chemoprevention of aflatoxin B-1 (AFB(1))-in duced hepatocarcinogenesis by oltipraz indicates that increased expression of phase 2 genes is of central importance, although inhibition of phase 1 a ctivation of AFB(1) can also contribute to protection. Exposure of rodents to 1,2-dithiole-3-thiones triggers nuclear accumulation of the transcriptio n 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-defici ent 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 chemopreventi on in humans, three key elements are necessary: a candidate agent, an at-ri sk population and modulatable inter-mediate endpoints. Towards this end, a placebo-controlled, double blind clinical trial of oltipraz was conducted i n residents of Qidong, PR China who are exposed to dietary aflatoxins and w ho are at high risk for the development of liver cancer. Oltipraz significa ntly enhanced excretion of a phase 2 product, aflatoxin-mercapturic acid, a derivative of the aflatoxin-glutathione conjugate, in the urine of study p articipants 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 AFB(1), AFM(1), when measured short ly after drug administration. While this study highlighted the general feas ibility of inducing phase 2 enzymes in humans, a longer term intervention i s addressing whether protective alterations in aflatoxin metabolism can be sustained for extended periods of time in this high-risk population. (C) 20 01 Elsevier Science B.V. All rights reserved.