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 B(1) (AFB(1))-induced hepatocarcinogenesis by
oltipraz indicates that increased expression of phase 2 genes is of central importance, although inhibition of phase 1 activation of AFB(1) 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 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 be sustained for extended periods of time in this high-risk population.