Chemoprevention by inducers of carcinogen detoxication enzymes

Abstract

One of the major mechanisms of chemical protection against carcinogenesis, mutagenesis, and other forms of toxicity mediated by electrophiles is the induction of enzymes involved in their metabolism, particularly phase 2 enzymes such as glutathione S-transferases (GSTs), uridine diphosphate-glucuronosyltransferases, and NAD(P)H:quinone reductase. Furthermore, induction of phase 2 enzymes appears to be a sufficient condition for obtaining chemoprevention and can be achieved in many target tissues by administering any of a diverse array of naturally occurring and synthetic chemical agents. One class of chemopreventive agents, 1,2-dithiole-3-thiones, was developed on the basis of their potent activity in rodent tissues as inducers of GSTs. A substituted dithiolethione, oltipraz [4-methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione], is an effective inhibitor of aflatoxin B1-mediated hepatocarcinogenesis in the rat. Oltipraz produces dramatic decreases in the levels of aflatoxin-DNA adducts in the liver as well as in the urinary levels of the depurination product aflatoxin-N7-guanine. Corresponding increases are seen in the biliary elimination of aflatoxin-glutathione conjugates. Administration of oltipraz results in 3- to 4-fold increases in hepatic cytosolic GST activities and mRNA levels for some alpha, mu and pi isoforms. Nuclear run-on assays have indicated that oltipraz treatment elevates rates of transcription of some GST subunits. In the rat, induction of phase 2 enzymes by oltipraz is mediated, at least in part, through the antioxidant response element in the 5' flanking region of these genes. Although oltipraz has a very short plasma half-life, elevations in the levels of some GST isoforms can persist up to 1 week after dosing with oltipraz. Concordantly, intermittent dosing schedules (i.e., once a week) are nearly as effective as daily interventions for inhibition of aflatoxin-mediated hepatic tumorigenesis. The protective efficacy of daily and weekly administration of oltipraz to people in Qidong, People's Republic of China, who are at high risk for aflatoxin exposure and subsequent development of hepetocellular carcinoma, is currently under evaluation.