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.