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Chemical Compound Review

Oltipraz     4-methyl-5-pyrazin-2-yl- dithiole-3-thione

Synonyms: Oltiprazum, Oltipraz [INN], CHEMBL178459, CCRIS 4048, AG-G-40846, ...
 
 
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Disease relevance of Oltipraz

 

Psychiatry related information on Oltipraz

 

High impact information on Oltipraz

  • CONCLUSIONS: Oltipraz-induced GSTA2 gene expression is dependent upon PI3-kinase-mediated nuclear translocation and binding of C/EBPbeta to the C/EBP response element in the GSTA2 gene promoter [8].
  • We investigated the role of the CCAAT/enhancer binding protein (C/EBP) in the induction of the GSTA2 gene (alpha class) by oltipraz and identified the enhancer element(s) responsible for GSTA2 gene expression [8].
  • Oltipraz treatment increased luciferase reporter-gene activity in H4IIE cells transfected with the C/EBP-containing regulatory region of the GSTA2 gene [8].
  • In oltipraz-treated cells, C/EBPbeta translocated to the nucleus and bound to the consensus sequence of C/EBP (TTGCGCAA) [8].
  • The goals of the present study were: to determine if oltipraz could induce detoxicating gene expression in human tissues; to identify effective non-toxic doses for more extensive clinical testing; and to establish a relationship between effects in the colon mucosa and those in a more readily available tissue, the peripheral mononuclear cell [1].
 

Chemical compound and disease context of Oltipraz

 

Biological context of Oltipraz

 

Anatomical context of Oltipraz

  • To determine whether these antioxidants can be similarly effective in human beings, we have investigated metabolism of AFB1, in primary human hepatocytes with or without pretreatment by oltipraz (OPZ), a synthetic derivative of the natural 1,2-dithiole-3-thione [17].
  • Preincubation of HT-29 cells with oltipraz enhanced the rate of removal of total platinum-DNA adducts and interstrand cross-links [14].
  • 1,2-Dithiole-3-thione was a less effective inhibitor and exhibited both a systemic toxicity and genotoxicity in alveolar macrophages, whereas its substituted analogue Oltipraz showed limited protective effects in this model [11].
  • In an attempt to further characterize the mechanism of CYP1A1 induction, we showed a rapid increase in intracellular calcium concentration upon treatment of Caco-2 cells with oltipraz [18].
  • We show here that, as previously found in rat lung and kidney, CYP1A1 is inducible by oltipraz in both rat intestine and Caco-2 cells, a cell line originated from a human colon adenocarcinoma [18].
 

Associations of Oltipraz with other chemical compounds

  • The effects of dietary oltipraz, fed during the initiation and postinitiation stages, on azoxymethane-induced colon carcinogenesis and on the levels of several detoxifying enzymes, namely, glutathione S-transferase, NAD(P)H:quinone reductase, and UDP-glucurinyl transferase activities, were studied in male F344 rats [15].
  • Treatment with oltipraz, an inducer of GST Alpha, partially overcomes the effect of HBx on both promoters [12].
  • In addition, IL-1 strongly suppressed the induction of rGSTA2 by 3-methylcholanthrene, oltipraz (a synthetic derivative of 1, 2-dithiole-3-thione), and phenobarbital and that of rGSTM1 by oltipraz and phenobarbital, whereas it was ineffective on rGSTP1 induction by these compounds [19].
  • Furthermore we demonstrated that resveratrol, an antagonist of the aryl hydrocarbon (Ah) receptor, inhibited the induction of both CYP1A1 promoter activity and mRNA by oltipraz, supporting the involvement of the Ah receptor in this induction [18].
  • Based on these results, the pharmacokinetics of oltipraz and metabolite III will be compared with the pharmacodynamic effects of orally administered oltipraz in a forthcoming phase I/II trial of oltipraz in patients with p24 antigenemia [13].
 

Gene context of Oltipraz

  • Dexamethasone-GR activation did not inhibit nuclear translocation of C/EBPbeta or Nrf2 nor their DNA binding activities induced by oltipraz or t-BHQ [20].
  • Inhibition of CYP1A2 and CYP3A4 by oltipraz results in reduction of aflatoxin B1 metabolism in human hepatocytes in primary culture [17].
  • Transcriptional induction of CYP1A1 by oltipraz in human Caco-2 cells is aryl hydrocarbon receptor- and calcium-dependent [18].
  • These data raise questions about the contribution of AHR and other secondary induction pathways in the mechanism of oltipraz [21].
  • Mechanism of rat UDP-glucuronosyltransferase 1A6 induction by oltipraz: evidence for a contribution of the Aryl hydrocarbon receptor pathway [21].
 

Analytical, diagnostic and therapeutic context of Oltipraz

  • In a randomized, placebo-controlled, double-blind phase IIa chemoprevention trial, we tested oltipraz, an antischistosomal drug that has been shown to be a potent and effective inhibitor of aflatoxin-induced hepatocarcinogenesis in animal models [22].
  • Moreover, the 2- to 5-fold induction of these enzymes in wild-type mice by the chemoprotective agent oltipraz, which is currently in clinical trials, was almost completely abrogated in the nrf2-deficient mice [23].
  • Oltipraz significantly reduced multiplicity of gastric neoplasia in wild-type mice by 55%, but had no effect on tumor burden in nrf2-deficient mice [23].
  • Northern blot analyses demonstrated that oltipraz did not alter the size of GST mRNA [9].
  • Quantitative HPLC analyses of GST subunits 24 h after 2 or 7 daily administrations of oltipraz showed that the levels of subunits Yb1, Yp, Yc2, and Ya2 were increased with maximum elevations of 5.6-, 11.1-, 6.4-, and 10.4-fold, respectively [24].

References

  1. Modulation of gene expression in subjects at risk for colorectal cancer by the chemopreventive dithiolethione oltipraz. O'Dwyer, P.J., Szarka, C.E., Yao, K.S., Halbherr, T.C., Pfeiffer, G.R., Green, F., Gallo, J.M., Brennan, J., Frucht, H., Goosenberg, E.B., Hamilton, T.C., Litwin, S., Balshem, A.M., Engstrom, P.F., Clapper, M.L. J. Clin. Invest. (1996) [Pubmed]
  2. Chemoprevention of hepatocellular carcinoma in aflatoxin endemic areas. Kensler, T.W., Egner, P.A., Wang, J.B., Zhu, Y.R., Zhang, B.C., Lu, P.X., Chen, J.G., Qian, G.S., Kuang, S.Y., Jackson, P.E., Gange, S.J., Jacobson, L.P., Muñoz, A., Groopman, J.D. Gastroenterology (2004) [Pubmed]
  3. Oltipraz, an inhibitor of human immunodeficiency virus type 1 replication. Prochaska, H.J., Yeh, Y., Baron, P., Polsky, B. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  4. Oltipraz may be useful in the prevention or treatment of Alzheimer's disease. Gharibzadeh, S., Hoseini, S.S., Mahdavi, S. Med. Hypotheses (2007) [Pubmed]
  5. Oltipraz treatment in experimental schistosomiasis mansoni. II. Effect of high dose oral therapy on worm load and process of copulation in infected mice. Aboul-Atta, A.M., Hassan, Z.A., el-Ahl, S.S. Journal of the Egyptian Society of Parasitology. (1989) [Pubmed]
  6. Pharmacokinetics of oltipraz after intravenous and oral administration in rats with dehydration for 72 hours. Bae, S.K., Lee, S.J., Kim, J.W., Kim, Y.H., Kim, S.G., Lee, M.G. Biopharmaceutics & drug disposition. (2005) [Pubmed]
  7. Induction of antioxidant genes in the brain as a therapeutic target in bipolar disorder: potential role of oltipraz. Emanuele, E., Olivieri, V., Aldeghi, A., Martinelli, V. Med. Hypotheses (2006) [Pubmed]
  8. Essential role of phosphatidylinositol 3-kinase-dependent CCAAT/enhancer binding protein beta activation in the induction of glutathione S-transferase by oltipraz. Kang, K.W., Cho, I.J., Lee, C.H., Kim, S.G. J. Natl. Cancer Inst. (2003) [Pubmed]
  9. Transcriptional control of glutathione S-transferase gene expression by the chemoprotective agent 5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione (oltipraz) in rat liver. Davidson, N.E., Egner, P.A., Kensler, T.W. Cancer Res. (1990) [Pubmed]
  10. Correspondence re: C.V. Rao, et al., Inhibition of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-induced lymphoma formation by oltipraz. Cancer Res., 56: 3395-3398, 1996. Roebuck, B.D., Rogers, A.E., Kensler, T.W. Cancer Res. (1997) [Pubmed]
  11. Modulation of biomarkers by chemopreventive agents in smoke-exposed rats. Izzotti, A., Balansky, R.M., Dagostini, F., Bennicelli, C., Myers, S.R., Grubbs, C.J., Lubet, R.A., Kelloff, G.J., De Flora, S. Cancer Res. (2001) [Pubmed]
  12. Modulation of glutathione S-transferase alpha by hepatitis B virus and the chemopreventive drug oltipraz. Jaitovitch-Groisman, I., Fotouhi-Ardakani, N., Schecter, R.L., Woo, A., Alaoui-Jamali, M.A., Batist, G. J. Biol. Chem. (2000) [Pubmed]
  13. Inhibition of human immunodeficiency virus type 1 replication by 7-methyl-6,8-bis(methylthio)pyrrolo[1,2-a]pyrazine, an in vivo metabolite of oltipraz. Prochaska, H.J., Bornmann, W.G., Baron, P., Polsky, B. Mol. Pharmacol. (1995) [Pubmed]
  14. The chemopreventive agent oltipraz stimulates repair of damaged DNA. O'Dwyer, P.J., Johnson, S.W., Khater, C., Krueger, A., Matsumoto, Y., Hamilton, T.C., Yao, K.S. Cancer Res. (1997) [Pubmed]
  15. Chemopreventive effect of oltipraz during different stages of experimental colon carcinogenesis induced by azoxymethane in male F344 rats. Rao, C.V., Rivenson, A., Katiwalla, M., Kelloff, G.J., Reddy, B.S. Cancer Res. (1993) [Pubmed]
  16. Oltipraz-mediated changes in aflatoxin B(1) biotransformation in rat liver: implications for human chemointervention. Buetler, T.M., Bammler, T.K., Hayes, J.D., Eaton, D.L. Cancer Res. (1996) [Pubmed]
  17. Inhibition of CYP1A2 and CYP3A4 by oltipraz results in reduction of aflatoxin B1 metabolism in human hepatocytes in primary culture. Langouët, S., Coles, B., Morel, F., Becquemont, L., Beaune, P., Guengerich, F.P., Ketterer, B., Guillouzo, A. Cancer Res. (1995) [Pubmed]
  18. Transcriptional induction of CYP1A1 by oltipraz in human Caco-2 cells is aryl hydrocarbon receptor- and calcium-dependent. Le Ferrec, E., Lagadic-Gossmann, D., Rauch, C., Bardiau, C., Maheo, K., Massiere, F., Le Vee, M., Guillouzo, A., Morel, F. J. Biol. Chem. (2002) [Pubmed]
  19. Modulation of glutathione S-transferase subunits A2, M1, and P1 expression by interleukin-1beta in rat hepatocytes in primary culture. Maheo, K., Antras-Ferry, J., Morel, F., Langouët, S., Guillouzo, A. J. Biol. Chem. (1997) [Pubmed]
  20. Glucocorticoid receptor (GR)-associated SMRT binding to C/EBPbeta TAD and Nrf2 Neh4/5: role of SMRT recruited to GR in GSTA2 gene repression. Ki, S.H., Cho, I.J., Choi, D.W., Kim, S.G. Mol. Cell. Biol. (2005) [Pubmed]
  21. Mechanism of rat UDP-glucuronosyltransferase 1A6 induction by oltipraz: evidence for a contribution of the Aryl hydrocarbon receptor pathway. Auyeung, D.J., Kessler, F.K., Ritter, J.K. Mol. Pharmacol. (2003) [Pubmed]
  22. Protective alterations in phase 1 and 2 metabolism of aflatoxin B1 by oltipraz in residents of Qidong, People's Republic of China. Wang, J.S., Shen, X., He, X., Zhu, Y.R., Zhang, B.C., Wang, J.B., Qian, G.S., Kuang, S.Y., Zarba, A., Egner, P.A., Jacobson, L.P., Muñoz, A., Helzlsouer, K.J., Groopman, J.D., Kensler, T.W. J. Natl. Cancer Inst. (1999) [Pubmed]
  23. Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice. Ramos-Gomez, M., Kwak, M.K., Dolan, P.M., Itoh, K., Yamamoto, M., Talalay, P., Kensler, T.W. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  24. Intermittent dosing with oltipraz: relationship between chemoprevention of aflatoxin-induced tumorigenesis and induction of glutathione S-transferases. Primiano, T., Egner, P.A., Sutter, T.R., Kelloff, G.J., Roebuck, B.D., Kensler, T.W. Cancer Res. (1995) [Pubmed]
 
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