Oltipraz and related dithiolethiones constitute an important class of chemopreventive agents that enhance the expression of
carcinogen detoxication and
antioxidant genes. Dose-response studies were undertaken to characterize the
cancer chemopreventive activities of several dithiolethiones that are at least as active as
oltipraz as inducers. Inhibition of formation of pre-neoplastic lesions and formation of
DNA adducts in livers of rats exposed to
aflatoxin B1 (AFB1) was monitored. In the
tumorigenesis experiment, the dithiolethiones were orally gavaged 3 days/week for 3 successive weeks and at four doses ranging from 0.03 to 0.3 mmol/kg body wt. AFB1 was gavaged beginning 1 week after the start of the dithiolethiones and for two successive weeks. The burden of AFB1-induced putative pre-neoplastic lesions (
glutathione S-transferase-placental
isoform positive foci) was quantified by light microscopy. Reduction in AFB-
DNA adduct burden was assessed 24 h following the first dose of AFB1. Both the parent
1,2-dithiole-3-thione (D3T) and its 5-tert-butyl derivative were more potent inhibitors than
oltipraz against these endpoints, while two of the seven tested analogs were slightly less inhibitory. D3T, the most potent dithiolethione of this series, was examined by microarray analysis for induction of hepatic genes at an intermediate chemopreventive dose (0.1 mmol/kg). Transcript levels of eight genes, including two known to detoxify
aflatoxin, namely,
glutathione S-transferase A5 (GSTA5) and AFB1
aldehyde reductase (AFAR) were elevated. Western analysis indicated that induction of hepatic GSTA5 and AFAR were directly related to the dose of D3T. At the highest dose of D3T (0.3 mmol/kg),
protein levels of GSTA5 and AFAR were induced by 7- and 27-fold, respectively. While efficacy in humans has yet to be tested, D3T is clearly more potent than
oltipraz and serves as a useful
molecular probe for determining the key events associated with protection by this class of agents.