Pharmacokinetic changes of oltipraz after intravenous and oral administration to rats with liver cirrhosis induced by dimethylnitrosamine

Bae, Soo Kyung; Lee, Shin J.; Lee, Jang Y.; Lee, Youngsoo; Lee, Inchul; Kim, Sang G.; Lee, Myung G.

doi:10.1016/j.ijpharm.2004.02.004

Cited by 21 publications

(48 citation statements)

References 42 publications

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“…Oltipraz at 3 to 100 M induced GSTA2 in H4IIE cells, and 30 M oltipraz was sufficient to almost maximally increase GSTA2 level (Kang et al, 2003), as confirmed by the present study. We have shown that the hepatic concentration of oltipraz 8 h after oral administration at a dose of 30 mg/kg to rats reached ϳ27 M, which was 12 times of the plasma concentration (Bae et al, 2004). Hence, it is conceivable that the oltipraz concentrations achieved in the liver may be within the concentration range used in the present study.…”

Section: Effects Of Oltipraz's Metabolites On C/ebp␤ and Nrf2mentioning

confidence: 52%

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DIFFERENTIAL EFFECTS OF THE OXIDIZED METABOLITES OF OLTIPRAZ ON THE ACTIVATION OF CCAAT/ENHANCER BINDING PROTEIN-β AND NF-E2-RELATED FACTOR-2 FOR GSTA2 GENE INDUCTION

Lee²,

Kim

et al. 2006

Drug Metab Dispos

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ABSTRACT:Comprehensive mechanistic studies suggest that oltipraz exerts cancer chemopreventive effects through the induction of glutathione S-transferase (GST). Previously, we have shown that the activation of CCAAT/enhancer binding protein-␤ (C/EBP␤), promoted by oltipraz, contributes to the transcriptional induction of the GSTA2 gene. Studies also indicated that exposure of animals to oltipraz triggers nuclear accumulation of NF-E2-related factor-2 (Nrf2) with an increase in Nrf2's antioxidant response element (ARE) binding activity. Given the previous reports that C/EBP␤ activation contributes to oltipraz's induction of the GSTA2 gene and that Nrf2 activation by oltipraz was variable depending on the concentrations, this study investigated whether the major oxidized metabolites of oltipraz induce GSTA2 through the activation of C/EBP␤ and/or Nrf2. Immunoblot analysis revealed that M1 Oltipraz [4-methyl-5-(2-pyrazinyl)-1,2-dithiol-3-thione] has been studied as a chemopreventive agent for malignancies, such as liver and colorectal cancer (Rao et al., 1993;Kensler, 1997). Comprehensive mechanistic studies indicate that oltipraz exerts cancer chemopreventive effects through the induction of glutathione S-transferases (GSTs) (Bolton et al., 1993;Kensler, 1997). GST induction also accounts for the cytoprotective effect of oltipraz against toxicantinduced injury (Jaitovitch-Groisman et al., 2000;Nelson et al., 2002). A phase IIa randomized chemoprevention trial of oltipraz in residents of Qidong, China, showed that oltipraz might be clinically active as a chemopreventive agent. In the human studies, oltipraz dosage regimens with higher doses and a long-dosing interval seemed to be more efficacious in preventing cancer, as supported by a significant decline in the levels of aflatoxin-albumin adduct in the individuals receiving a higher dose of oltipraz (500 mg/week) (Jacobson et al., 1997;Jackson and Groopman, 1999;Wang et al., 1999).Exposure of experimental animals to oltipraz triggers nuclear accumulation of NF-E2-related factor-2 (Nrf2) Iida et al., 2004) and enhances Nrf2's antioxidant response element (ARE) binding activity (Pietsch et al., 2003). Diminished expression of phase II enzyme genes by oltipraz in the Nrf2 Ϫ/Ϫ mice supports the role of Nrf2 activation in its cancer chemopreventive effects Ramos-Gomez et al., 2001). Molecular signals activated by oxidative stress stimulate translocation of Nrf2 to the nucleus, where it binds and activates the AREs located in the promoter regions of phase II enzyme genes (Moinova and Mulcahy, 1998;Venugopal and Jaiswal, 1998;Huang et al., 2000).Studies from this laboratory showed that oltipraz at clinically relevant concentrations marginally increased the band intensity of Nrf2 ARE binding and thus weakly enhanced the accumulation of Nrf2 in the nucleus. Our results suggested that GSTA2 induction by oltipraz might be mediated by the activation of other transcriptional Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.doi:10...

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Section: Effects Of Oltipraz's Metabolites On C/ebp␤ and Nrf2mentioning

confidence: 52%

“…Because of the high lipid solubility of oltipraz, the pharmacokinetics of oltipraz show a tendency toward accumulation in organs, especially liver and large intestine (Bae et al, 2004). Hence, it is likely that oltipraz at high concentrations stays longer in the body, thereby increasing the production of its metabolites.…”

mentioning

confidence: 99%

DIFFERENTIAL EFFECTS OF THE OXIDIZED METABOLITES OF OLTIPRAZ ON THE ACTIVATION OF CCAAT/ENHANCER BINDING PROTEIN-β AND NF-E2-RELATED FACTOR-2 FOR GSTA2 GENE INDUCTION

Lee²,

Kim

et al. 2006

Drug Metab Dispos

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“…As reported by others and ourselves, the daily dose of oltipraz required to effectively treat cirrhosis in humans is approximately 100 mg, and its estimated upper plasma C max in clinical situations is approximately 1.7 M. 18 Because levels of oltipraz in liver tissue are 20-fold greater than in plasma, 18 the concentration required for the effective inhibition of insulin resistance appears to be pharmacologically achievable in target tissue.…”

Section: Discussionmentioning

confidence: 97%

Identification of a novel class of dithiolethiones that prevent hepatic insulin resistance via the adenosine monophosphate–activated protein kinase–p70 ribosomal S6 kinase-1 pathway

et al. 2007

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Several established liver diseases of various causes are highly associated with hepatic insulin resistance, which is characterized by the desensitization of target cells to insulin. Peripheral insulin resistance is observed in most patients who have cirrhosis. Conversely, insulin-resistant diabetic patients are at increased risk for developing liver disease. Current therapeutic interventions in insulin resistance are limited and therefore likely to be advanced by new tailor-made drugs. Oltipraz, a prototype dithiolthione, inhibits transforming growth factor ␤1 and has the ability to regenerate cirrhotic liver. We investigated the effects of oltipraz and synthetic dithiolthiones on hepatic insulin resistance and the molecular basis of action. Oltipraz and other dithiolethione compounds were tested on tumor necrosis factor ␣ (TNF-␣)-induced insulin resistance and glucose homeostasis in vitro and in vivo via immunoblotting, plasmid transfection, kinase analysis, and functional assays. Oltipraz treatment inhibited the ability of TNF-␣ to activate p70 ribosomal S6 kinase-1 (S6K1) downstream of mammalian target of rapamycin, thus preventing insulin receptor substrate-1 serine phosphorylation and protecting insulin signals. Moreover, oltipraz activated AMP-activated protein kinase (AMPK), whose inhibition by a dominant negative mutant abolished S6K1 inhibition and protected insulin signaling, indicating that AMPK activation leads to S6K1 inhibition. In hepatocyte-derived cell lines, oltipraz inhibited glucose production. Oltipraz prevented hepatic insulin resistance in C57BL/6 mice challenged with endotoxin (or TNF-␣), leptin-deficient mice, and mice fed a high-fat diet. Synthetic dithiolethiones comparably inhibited insulin resistance. Conclusion: Our findings led to the identification of dithiolethione compounds that prevent insulin resistance through a mechanism involving AMPK-mediated S6K1 inhibition and thereby sensitize hepatic insulin response. (HEPATOLOGY 2007;46:730-739.)

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“…In human studies conducted in Qidong, China, oltipraz treatment regimens with higher doses and a long-dosing interval were efficacious in preventing hepatocellular carcinoma (Jacobson et al, 1997), which is supported by the decreases in median levels of the phase 1 metabolite aflatoxin M 1 excreted in the urine of individuals receiving a higher dose of oltipraz (500 mg/week) (Wang et al, 1999). Because of lipophilicity, oltipraz tends to accumulate in several organs (Bae et al, 2004). Hence, treatment at higher concentrations may allow oltipraz to reside for a longer time in the body and result in the production of more of its metabolites.…”

Section: Discussionmentioning

confidence: 99%

“…Oltipraz tends to accumulate in organs, especially liver, large intestine, and fat because of its lipophilicity (Bae et al, 2004). At high concentrations, oltipraz residence time in the body is prolonged, which may increase the production of its oxidized metabolites via extensive metabolism by the two major pathways common to various mammalian species: first, oxidative desulfuration of the thione to yield M1, which does not seem to be metabolized further; and second, desulfuration, methylation, and molecular rearrangement to yield M2, which can be metabolized to other oxidized forms, M3 and M4 (Bieder et al, 1983;O'Dwyer et al, 1997).…”

mentioning

confidence: 99%

Oxidized Metabolites of Oltipraz Exert Cytoprotective Effects against Arachidonic Acid through AMP-Activated Protein Kinase-Dependent Cellular Antioxidant Effect and Mitochondrial Protection

Kwon

Shin²,

Cho³

et al. 2009

Drug Metab Dispos

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Pharmacokinetic changes of oltipraz after intravenous and oral administration to rats with liver cirrhosis induced by dimethylnitrosamine

Cited by 21 publications

References 42 publications

DIFFERENTIAL EFFECTS OF THE OXIDIZED METABOLITES OF OLTIPRAZ ON THE ACTIVATION OF CCAAT/ENHANCER BINDING PROTEIN-β AND NF-E2-RELATED FACTOR-2 FOR GSTA2 GENE INDUCTION

DIFFERENTIAL EFFECTS OF THE OXIDIZED METABOLITES OF OLTIPRAZ ON THE ACTIVATION OF CCAAT/ENHANCER BINDING PROTEIN-β AND NF-E2-RELATED FACTOR-2 FOR GSTA2 GENE INDUCTION

Identification of a novel class of dithiolethiones that prevent hepatic insulin resistance via the adenosine monophosphate–activated protein kinase–p70 ribosomal S6 kinase-1 pathway

Oxidized Metabolites of Oltipraz Exert Cytoprotective Effects against Arachidonic Acid through AMP-Activated Protein Kinase-Dependent Cellular Antioxidant Effect and Mitochondrial Protection

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