Identification of dithiolethiones with better chemopreventive properties than oltipraz
Y Y Maxuitenko1, A H Libby, H H Joyner
1Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH 03755, USA.
Abstract:
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.
Insights
New dithiolethiones show greater cancer chemopreventive potential than oltipraz. Researchers identified compounds that effectively inhibit aflatoxin B1 hepatotoxicity and prevent tumor development in rats.
Area of Science:
- Chemoprevention research
- Hepatotoxicity studies
- Drug discovery
Background:
- Oltipraz and dithiolethiones are known chemopreventive agents.
- Identifying more potent dithiolethiones is crucial for cancer prevention.
- Enzyme induction is a key mechanism for chemoprevention.
Purpose of the Study:
- To identify dithiolethiones with enhanced chemopreventive activity compared to oltipraz.
- To evaluate the in vivo enzyme induction and hepatotoxicity inhibition of various dithiolethiones.
- To assess the efficacy of selected dithiolethiones in preventing aflatoxin B1-induced tumorigenesis.
Main Methods:
- 17 dithiolethiones were analyzed for their ability to induce hepatic phase II enzymes (NAD(P)H:quinone reductase and glutathione S-transferase) in vivo.
- Dithiolethiones were tested for their ability to inhibit acute hepatotoxicity induced by aflatoxin B1 (AFB1) in rats.
- Nine promising dithiolethiones were further evaluated for their efficacy in preventing AFB1-induced hepatic tumorigenesis.
Main Results:
- 15 out of 17 dithiolethiones showed greater induction of NAD(P)H:quinone reductase than oltipraz.
- 11 dithiolethiones demonstrated greater induction of glutathione S-transferase compared to oltipraz.
- Six dithiolethiones were found to be significantly more effective than oltipraz in preventing AFB1-induced tumorigenesis, correlating with their hepatotoxicity inhibition capabilities.
Conclusions:
- Several dithiolethiones exhibit superior chemopreventive activity against AFB1-induced tumorigenesis compared to oltipraz.
- Inhibition of acute hepatotoxicity by AFB1 is a reliable indicator of chemopreventive efficacy.
- These findings identify novel dithiolethiones as promising candidates for further cancer chemoprevention research.
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