Structure-activity relationships in the induction of Phase II enzymes by derivatives of 3H-1,2-dithiole-3-thione in rats

Derivatives of 3H-1,2-dithiole-3-thione (D3T) decrease the incidence and multiplicity of tumours in animals exposed to chemical carcinogens by a mechanism that is believed to involve their ability to increase tissue activities of Phase II detoxification enzymes. One D3T derivative, 4-methyl-5-pyrazinyl-3H-1,2-dithiole-3-thione (oltipraz) has been investigated as a chemopreventative agent in humans, although large-scale trials of this substance were abandoned because of toxicity problems. While detailed information on the inductive ability of oltipraz is available, little is known of the relative activity of other D3T derivatives in vivo. In the present study, the effects of 10 dithiolethiones on the activities of two Phase II enzymes, NAD(P)H:quinone acceptor oxidoreductase and glutathione S-transferase, have been determined in a number of rat tissues. In all tissues, oltipraz was a relatively weak inducer. D3T itself and 5-methyl-, 4-chloro-5-methyl-, 4-phenyl- and 5,6-dihydrocyclopenta[c]-1,2-dithiole-3-thione (cyclopenta) were the most active compounds, both in terms of degree of induction and the number of organs in which enzyme induction occurred. Cyclopenta was a potent enzyme inducer in the urinary bladder, whereas 4-chloro-5-methyl-3H-1,2-dithiole-3-thione was particularly effective in the liver and the 4-phenyl derivative showed high inductive activity in the lungs. Comparison of the inducer activities of selected dithiolethiones, including cyclopenta, in cultured bladder carcinoma cells in vitro showed strong correlation with the in vivo data, suggesting that the different inducer activity of the dithiolethiones in vivo, at least in the bladder, is an intrinsic property of these compounds. In view of the evidence that Phase II enzyme induction plays a major role in the chemoprotective action of dithiolethiones, evaluation of the anti-cancer activity of the more potent inducers identified in this study would be of interest.