Oltipraz and related dithiolethiones are an important class of chemopreventive agents. Studies were undertaken to identify cancer chemopreventive dithiolethiones more active than oltipraz. Largely based upon enzyme induction activities in vitro, 17 dithiolethiones, including oltipraz, were analyzed for their ability to induce hepatic phase II enzyme activities in vivo. Of these compounds, 15 produced greater induction of NAD(P)H:quinone reductase and 11 yielded greater induction of glutathione S-transferase than oltipraz. All 17 dithiolethiones were then tested for their ability to inhibit acute hepatotoxicity by aflatoxin B1 (AFB1), which previously has been shown to be an intermediate predictor of chemopreventive activity. Rats were pretreated with dithiolethiones (0.3 mmol/kg body wt, three times a week per os) and challenged with two acutely toxic doses of AFB1 (0.5 mg/kg body wt, once daily for two successive days per os). Inhibition of hepatotoxicity was measured by changes in body weight gain during AFB1 challenge, reduction 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 prevent AFB1-induced tumorigenicity, as assessed by a reduction in hepatic burden of putative preneoplastic foci. Six dithiolethiones were found to be considerably more effective than oltipraz in preventing AFB1-induced tumorigenesis. In general, dithiolethiones that were very effective in inhibition of acute hepatotoxicity were also found to be effective in prevention of hepatic tumorigenesis.

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Abstract-Thousands of waterfowl deaths occurring at Eagle River Flats (ERF), Anchorage, Alaska, USA, have been attributed to the ingestion of white phosphorus (P 4 ) particles. White phosphorus has been found in the egg of one herring gull (Larus argentatus) and in the yolks of some shorebirds at ERF. The presence of P 4 in eggs suggests potential toxic consequences for avian reproduction. This study was undertaken to determine the magnitude and potential importance of P 4 translocation from the hen to the egg. Egglaying hens (Gallus domesticus) were gavaged with a single dose of 1, 3, or 5 mg P 4 /kg body weight or dosed with 1 mg P 4 /kg body weight for 5 consecutive d. Eggs of dosed hens were collected daily. White phosphorus was extracted from the yolk and the white, individually, with isooctane and analyzed by gas chromatography. White phosphorus had no significant effect on chicken weight, egg weight, or shell thickness. However, laying frequency was significantly reduced (p Ͻ 0.05) in chickens receiving 1 mg P 4 /kg body weight for 5 d. For all treatments, P 4 was detected in the yolk and not in the white. It was first detected in the yolk approx. 1 to 2 d after P 4 exposure and became nondetectable 6 to 10 d after P 4 exposure. The total P 4 recovered from eggs of chickens treated with P 4 was less than 0.01% of the administered dose.

Previous studies have demonstrated that ingestion of 5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione (oltipraz) during the aflatoxin B1 (AFB1) treatment phase completely prevented hepatic cancer. In this study we evaluated the effect of feeding oltipraz during the post-AFB1 treatment phase. Fifty-five male F344 rats were divided into five groups. All rats were gavaged with 25 micrograms AFB1/rat, five times a week for two successive weeks. The rats were fed the oltipraz-supplemented diet according to three different feeding regimes: during the AFB1 treatment phase (1 week prior to, during and 1 week after the last gavage with AFB1); during the post-treatment phase; or throughout the entire time of the experiment. Phenobarbital-supplemented diet was fed during post-treatment phase to one group and this was used as a positive control for the promotion of AFB1-induced focal growth. The burden of putative, preneoplastic, hepatic glutathione S-transferase P-positive foci was evaluated at 13 weeks after the AFB1 treatment phase. As seen previously, oltipraz fed during the AFB1 treatment phase significantly inhibited focal development, i.e. the volume percent of the liver occupied with foci was reduced by 87%. Oltipraz when fed during the post-treatment phase neither inhibited nor enhanced focal development.