fumarates and oltipraz

Phase II detoxifying enzymes like NAD(P)H (quinone acceptor)oxidoreductase1 (NQO1), glutathione S-transferases (GST), and UDP-glucuronyltransferases (UGT) may play an important role in preventing carcinogen-induced cancers. Inducers of these enzymes have been shown to inhibit carcinogen-induced colon tumors in rat and mouse models. However, it has not been clearly demonstrated that NQO1 contributes to this effect. We examined the effect of NQO1 inducers on colon carcinogenesis using an aberrant crypt foci (ACF) rat model. Sprague-Dawley rats were fed control diet or diet containing 400 ppm dimethyl fumarate or 200 ppm oltipraz for 7 days, and Phase II enzymes in rat colon and liver were measured. Dimethyl fumarate significantly increased NQO1 and GST activities in colon and liver but did not increase UGT activities in these tissues. In contrast, oltipraz significantly increased NQO1 activities in colon and liver and produced a small increase in GST activity in the liver but did not increase GST activity in the colon or UGT activities in the liver or colon. Sprague Dawley rats were fed control diet or diet containing 200 ppm oltipraz and then treated with the carcinogens azoxymethane or methyl nitrosourea. Both carcinogens produced ACF in all of the rat colons, but rats fed oltipraz diet had significantly fewer ACF than those fed control diet. This protective effect was reversed in rats treated with the NQO1 inhibitor, dicoumarol. However, treatment with oltipraz did not alter the distribution of crypt multiplicities in the ACF. These studies demonstrated that induction of NQO1 plays a significant role in inhibiting initiation of carcinogen-induced ACF in Sprague-Dawley rats. This provides the first direct evidence that NQO1 may play a role in preventing colon cancer. The study also found that oltipraz added to the diet of Sprague-Dawley rats selectively increased NQO1 activity in colon mucosa with no increase in GST and UGT activities in these tissues. Thus, this model will be useful for further investigating the role of NQO1 in prevention of colon cancer.

Topics: Animals; Anticarcinogenic Agents; Carcinogens; Colon; Colonic Neoplasms; Dimethyl Fumarate; Disease Models, Animal; Enzyme Induction; Fumarates; Glucuronosyltransferase; Glutathione Transferase; Inactivation, Metabolic; Intestinal Mucosa; Liver; Male; NAD(P)H Dehydrogenase (Quinone); NADP; Pyrazines; Radiation-Sensitizing Agents; Rats; Rats, Sprague-Dawley; Thiones; Thiophenes

Supplementation of media with high concentrations of thiols (5-20 mM) inhibits human immunodeficiency virus type 1 (HIV-1) replication in vitro. Compounds that prevent carcinogenesis via induction of phase II enzymes also elevate intracellular GSH levels, thus raising the possibility that chemopreventive enzyme inducers may represent a more pharmacologically feasible method to inhibit viral replication. Previous studies revealed that oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione] was the only GSH inducer tested that could inhibit HIV-1 replication in acutely infected H9 cells. Because thiols are proposed to suppress transcription of the integrated HIV-1 genome by preventing the activation of nuclear factor-kappa B, experiments evaluating inducers of GSH levels in acutely infected H9 cells do not rule out the ability of these compounds to inhibit viral replication in chronically infected cells exposed to cytokines or mitogens. Therefore, we determined the antiviral effects of several inducers in phorbol-12-myristate-13- acetate-stimulated U1 cells, a monocytoid cell line that contains two integrated copies of the HIV-1 genome. Although 1,2-dithiole-3-thione, dimethyl fumarate, and oltipraz can elevate cytosolic thiol levels, only oltipraz inhibited HIV-1 replication. Moreover, decreased nuclear factor-kappa B binding activity could be correlated with increases in cytosolic thiols produced by various treatments (r2 = 0.8) but not with suppression of viral replication (r2 = 0.01). These data suggest that oltipraz-induced increases in GSH are not responsible for the antiviral action of oltipraz and that elevation of intracellular GSH levels by chemopreventive enzyme inducers does not inhibit viral replication.

Topics: Antiviral Agents; Cell Line; Dimethyl Fumarate; Dithiothreitol; Enzyme Induction; Fumarates; Glutathione; HIV-1; Monocytes; NAD(P)H Dehydrogenase (Quinone); NF-kappa B; Pyrazines; Sulfhydryl Compounds; Tetradecanoylphorbol Acetate; Thiones; Thiophenes; Virus Replication