RESUMO
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.
Assuntos
Anticarcinógenos/farmacologia , Pirazinas/farmacologia , Aflatoxina B1/toxicidade , Animais , Indução Enzimática/efeitos dos fármacos , Fígado/efeitos dos fármacos , Neoplasias Hepáticas Experimentais/prevenção & controle , Masculino , Ratos , Ratos Endogâmicos F344 , Tionas , TiofenosRESUMO
4-Methyl-5-pyrazinyl-3H-1,2-dithiole-3-thione (oltipraz) and several other dithiolethiones protect against the acute toxicities of many xenobiotics and are effective inhibitors of experimental carcinogenesis. These protective effects are mediated, in part, through elevation of glutathione S-transferase, NAD(P)H: quinone reductase and UDP-glucuronosyltransferase activities in the liver and other target tissues. The induction of these phase 2 enzymes by oltiprax results from enhanced transcription. In the present study, the molecular mechanisms of these inductions were analyzed utilizing a construct containing a 41 bp enhancer element derived from the 5'-upstream region of the mouse liver glutathione S-transferase Ya subunit gene ligated to the 5' end of the isolated promoter region of this gene, and inserted into a plasmid containing a human growth hormone reporter gene. When this construct was transfected into murine Hepa 1c1c7 hepatoma cells, the concentrations of 25 dithiolethiones and related analogs required to double growth hormone production were determined and spanned a range nearly three orders of magnitude. Concentrations of dithiolethiones required to double the specific activity of NAD(P)H: quinone reductase were also determined in Hepa 1c1c7 cells. There was a positive correlation (r = 0.78) between the potencies of the 21 active compounds as inducers of both NAD(P)H: quinone reductase activity and growth hormone production. Moreover, no dithiolethiones were inactive in only one system. It is probable, therefore, that the induction of NAD(P)H: quinone reductase and other phase 2 enzymes by oltipraz and other dithiolethiones is mediated entirely through the 41 bp enhancer element.