Role of phase 2 enzyme induction in chemoprotection by dithiolethiones

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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.

Section snippets

Role of enzyme induction in cancer chemoprotection

Chemical protection against toxins and carcinogens can be successfully achieved through several different mechanisms [1], [2]. Indeed, chemical agents and natural products with cancer chemoprotective activity encompass diverse classes of molecules with varied biological effects including anti-mutagenic, antioxidant, anti-inflammatory, and anti-hormonal activity [3], [4]. One strategy of chemoprotection that has proven to be particularly efficacious in experimental systems is the modulation of

Protection against experimental carcinogenesis by dithiolethiones

The biochemical manifestations of oltipraz in schistosome-infected mice prompted Bueding to predict that this drug might have cancer chemoprotective properties. The initial confirmation that 1,2-dithiole-3-thiones such as oltipraz may exert chemoprotective effects in vivo came from the demonstration that oltipraz protected against the hepatotoxicity of carbon tetrachloride and acetaminophen in mice [23]. Subsequent studies have demonstrated protection by oltipraz against the acute

Mechanisms of phase 2 enzyme induction by dithiolethiones

Initial molecular studies in rats and subsequent studies in humans indicated that increases in mRNA and protein levels of several phase 2 genes in response to dithiolethiones and other chemoprotective agents were mediated through the transcriptional activation of these genes [32], [33]. Two families of phase 2 enzyme inducers exist. Prochaska and Talalay [34] have coined the terms bifunctional and monofunctional inducers to describe these families. Bifunctional inducers (e.g. polycyclic

Clinical studies with dithiolethiones

Phase I clinical trials are designed to characterize the pharmacokinetics and tolerableness of the chemopreventive agent [55]. Dose and schedule of administration are based on achieving plasma drug levels that are very likely to be safe and likely to show effectiveness based upon preclinical studies in in vivo and in vitro models. Single dose phase I studies with oltipraz indicated that administration of 500 mg orally would produce a peak plasma concentration of about 20 μM while 125 mg produced a

Acknowledgements

We gratefully acknowledge support for our work in protection against cancer from the National Cancer Institute (CA39416, CA44530, CA77130 and Center Grant CA06973) and the National Institute of Environmental Health Sciences (ES06052 and Center Grant ES03819).

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