IDENTIFICATION OF DITHIOLETHIONES WITH BETTER CHEMOPREVENTIVE PROPERTIES THAN OLTIPRAZ

Oltipraz and related dithiolethiones are an important class of chemopr eventive agents, Studies were undertaken to identify cancer chemopreve ntive dithiolethiones more active than oltipraz, Largely based upon en zyme induction activities in vitro, 17 dithiolethiones, including olti praz, were analyzed for their ability to induce hepatic phase II enzym e activities in vivo, Of these compounds, 15 produced greater inductio n of NAD(P)H:quinone reductase and 11 yielded greater induction of glu tathione S-transferase than oltipraz, All 17 dithiolethiones were then tested for their ability to inhibit acute hepatotoxicity by affatoxin B-1 (AFB(1)), which previously has been shown to be an intermediate p redictor of chemopreventive activity, Rats were pretreated with dithio lethiones (0.3 mmol/kg body wt, three times a week per os) and challen ged with two acutely tor;ic doses of AFB(1) (0.5 mg/kg body wt, once d aily for two successive days per os). Inhibition of hepatotoxicity was measured by changes in body weight gain during AFB1 challenge, reduct ion in levels of hepatic enzymes in serum and diminution of bile duct cell proliferation, Nine dithiolethiones spanning a range of responses in this toxicity screen were further tested for their ability to prev ent AFB(1)-induced tumorigenicity, as assessed by a reduction in hepat ic burden of putative preneoplastic foci, Six dithiolethiones were fou nd to be considerably more effective than oltipraz in preventing AFB1- induced tumorigenesis, In general, dithiolethiones that were very effe ctive in inhibition of acute hepatotoxicity were also found to be effe ctive in prevention of hepatic tumorigenesis.