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PubMed1995

Effect of troglitazone (CS-045) and bezafibrate on glucose tolerance, liver glycogen synthase activity, and beta-oxidation in fructose-fed rats.

To clarify the relationship between lipid and glucose metabolism abnormalities in fructose-fed rats, we examined whether an improvement of insulin sensitivity by troglitazone (CS-045) or a decrease in plasma lipids by bezafibrate affects the relationship between serum levels of lipid and glucose. In addition, we also examined changes in liver glycogen metabolism and beta-oxidation in fructose-fed rats. Troglitazone ameliorated fasting hyperlipidemia, hyperglycemia, and hyperinsulinemia. In addition, it augmented glycogen synthase activity by 53%, and decreased the mitochondrial palmitic acid beta-oxidation rate and ketone body production rate by 27% and 55%, respectively. However, hyperglycemia and liver glycogen synthase activity were not improved by bezafibrate treatment despite a marked reduction of serum triglyceride (TG) levels resulting from a 1.76-fold increase in mitochondrial oxidation and a 2.04-fold increase in hepatic ketone body production. These results suggest that abnormalities in glucose and lipid metabolism in fructose-fed rats, which are ameliorated by troglitazone, may be closely linked to reduced glycogen synthase activity in the liver.

Animals↗
PubMed2004

Fucoxanthin induces apoptosis and enhances the antiproliferative effect of the PPARgamma ligand, troglitazone, on colon cancer cells.

The effect of fucoxanthin, from the edible seaweed Undaria pinnatifida on viability of colon cancer cells and induction of apoptosis was investigated. Fucoxanthin remarkably reduced the viability of human colon cancer cell lines, Caco-2, HT-29 and DLD-1. Furthermore, treatment with fucoxanthin induced DNA fragmentation, indicating apoptosis. The DNA fragmentation in Caco-2 cells treated with 22.6 microM fucoxanthin for 24 h was 10-fold higher than in the control. Fucoxanthin suppressed the level of Bcl-2 protein. Also, DNA fragmentation induced by fucoxanthin was partially inhibited by a caspase inhibitor Z-VAD-fmk. Moreover, combined treatment with 3.8 microM fucoxanthin and 10 microM troglitazone, which is a specific ligand for peroxisome proliferator-activated receptor (PPAR) gamma, effectively decreased the viability of Caco-2 cells. However, separate treatments with these same concentrations of fucoxanthin nor troglitazone did not affect cell viability. These findings indicate that fucoxanthin may act as a chemopreventive and/or chemotherapeutic carotenoid in colon cancer cells by modulating cell viability in combination with troglitazone.

Antineoplastic Agents↗
PubMed2004

Uniformity and physical states of troglitazone in solid dispersions determined by electron probe microanalysis and microthermal analysis.

Solid dispersions of troglitazone with PVP K30 in a weight ratio of 1:2 were prepared by the closed melting method. Solid dispersions that exhibit different degrees of crystallinity (0 and 36%) were prepared by changing the charged amount of water, which functions as a plasticizer for PVP K30. Electron probe microanalysis (EPMA) and microthermal analysis (micro TA) of the solid dispersions were performed to investigate the uniformity and physical state of troglitazone in the solid dispersions. The EPMA study confirmed that troglitazone was dispersed homogeneously in the sample whose apparent crystallinity was 0%. However, the sample with a 36% crystallinity was heterogeneous. The micro TA study showed that the sample with a 36% crystallinity was present in two states, crystal and amorphous. EPMA and micro TA would be useful tools to confirm the uniformity and physical states, respectively, of solid dispersions.

Chemistry, Pharmaceutical↗
PubMed2005

The peroxisome proliferator-activated receptor gamma ligand troglitazone induces apoptosis and p53 in rat granulosa cells.

PPARgamma is expressed in both the rodent and human ovary, but the endogenous activation state of PPARgamma in the ovary and its normal role in ovarian function remain unclear. Here, we investigated mRNA and protein expression as well as DNA-binding activity of PPARgamma during follicle growth and luteinization in the immature, gonadotropin-primed rat model. Gel shift analysis demonstrated binding of ovarian PPAR to a consensus peroxisome proliferator response element (PPRE) that was supershifted with an antibody specific for PPARgamma, but not with antibodies specific for PPARalpha or beta/delta. PPARgamma expression and DNA-binding activity was highest 0-12 h post-PMSG, but declined during later stages of follicle growth (24-36 h post-PMSG). Administration of hCG induced a decline in PPARgamma mRNA, protein, and DNA-binding activity beginning at 4 h. Treatment of preovulatory granulosa cells with the PPARgamma ligand troglitazone (1-10 microM) in vitro decreased cell viability, increased sub-G1 apoptosis, and reduced DNA synthesis. Troglitazone induced p53 protein expression and decreased bcl-2 mRNA, suggesting possible mechanisms for troglitazone-induced apoptosis. These data indicate that PPARgamma is in the ovary is capable of binding DNA in the absence of pharmacological activation and provide evidence for a possible physiologic role for this receptor in regulating granulosa cell survival.

Animals↗
PubMed2003

Troglitazone stimulates IGF-binding protein-1 by a PPAR gamma-independent mechanism.

IGFBP-1 modulates IGF availability for glucose homeostasis and it may also play a paracrine role in hepatocyte survival. IGFBP-1 is inhibited transcriptionally by insulin and is also regulated by a number of pathways that influence hepatic insulin sensitivity. The effect of the thiazolidinedione troglitazone on IGFBP-1 production was studied in HepG2 human hepatoma cells, which were found to express PPAR alpha, PPAR gamma, and PXR. Troglitazone stimulated IGFBP-1 mRNA expression 2-fold within 3h of exposure (P<0.001) and stimulated secretion up to 3-fold over a narrow dose range within 24h (P<0.001). This effect was mimicked by the PXR ligands clotrimazole and phenobarbital, but not by Wy14,643 or rosiglitazone, which are ligands for PPAR alpha and -gamma, respectively. We conclude that the effect of troglitazone on IGFBP-1 production by HepG2 cells is independent of PPAR and may involve PXR.

Carcinoma, Hepatocellular↗
PubMed2002

Troglitazone does not protect rat pancreatic beta cells against free fatty acid-induced cytotoxicity.

Thiazolidinediones are a novel class of antidiabetic drugs that reduce insulin resistance through interaction with nuclear peroxisome proliferator-activated receptor (PPAR)gamma. One of these agents, troglitazone, was also proposed to protect beta cells against FFA-induced toxicity, but this effect has not yet been directly demonstrated. We recently reported in vitro conditions under which free fatty acids (FFA) cause beta cell death by necrosis or apoptosis. The present study investigates whether troglitazone (10 microM) interferes with this FFA-induced toxicity. Addition of this compound did not protect against oleate- or palmitate-induced toxicity. On the contrary, it increased palmitate-induced necrosis during the first two days of culture, and elevated (increase by 10-20%, P<0.05) both oleate- and palmitate-induced apoptosis after 8 days. These results do not support the view that troglitazone exerts a direct protective effect on beta cells that are exposed to cytotoxic FFA concentrations. They instead indicate that the agent may sensitize pancreatic beta cells to FFA-induced damage, raising the possibility that its use facilitates the deleterious effect of increased FFA levels on the pancreatic beta cell mass.

Animals↗
PubMed1999

Differential block by troglitazone and rosiglitazone of glibenclamide-sensitive K(+) current in rat aorta myocytes.

Thiazolidinediones are insulin-sensitising agents effective in controlling type II diabetes. These compounds also cause vasodilation. We evaluated the effects of the thiazolidinediones troglitazone and rosiglitazone on the glibenclamide-sensitive K(+) current in freshly isolated rat aorta myocytes. Troglitazone inhibited this current in a concentration-dependent manner (IC(50) approximately 1 microM). Rosiglitazone had a similar, but much less potent (IC(50) approximately 20 microM) action. Block of the glibenclamide-sensitive K(+) channels, in particular by troglitazone, may potentially affect the response of arteries to hypoxia and to certain endogenous and exogenous vasodilators.

Animals↗
PubMed2001

15-Deoxy-delta12,14-PGJ2, but not troglitazone, modulates IL-1beta effects in human chondrocytes by inhibiting NF-kappaB and AP-1 activation pathways.

The activation of peroxisome proliferator-activated receptor gamma (PPARgamma) has been shown to inhibit the production and the effects of proinflammatory cytokines. Since interleukin-1beta (IL-1beta) directly mediates cartilage degradation in osteoarthritis, we investigated the capability of PPARgamma ligands to modulate IL-1beta effects on human chondrocytes. RT-PCR and Western blot analysis revealed that PPARgamma expression was decreased by IL-1beta. 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), in contrast to troglitazone, was highly potent to counteract IL-1beta-induced cyclooxygenase-2 and inductible nitric oxide synthase expression, NO production and the decrease in proteoglycan synthesis. Western blot and gel-shift analyses demonstrated that 15d-PGJ2 inhibited NF-kappaB activation, while troglitazone was ineffective. Although 15d-PGJ2 attenuated activator protein-1 binding on the DNA, it potentiated c-jun migration in the nucleus. The absence or the low effect of troglitazone suggests that 15d-PGJ2 action in human chondrocytes is mainly PPARgamma-independent.

Active Transport, Cell Nucleus↗
PubMed2000

Troglitazone and related compounds: therapeutic potential beyond diabetes.

Troglitazone and structurally related compounds (pioglitazone, rosiglitazone etc.) containing thiazolidinediones (TZD) are a novel class of antidiabetic agents which decrease blood glucose in diabetic animal models and in patients with Non-Insulin-Dependent Diabetes Mellitus (NIDDM) through alleviating insulin resistance. A large body of evidence is now accumulating indicating that insulin resistance and/or resulting hyperinsulinemia underlie the pathogenesis of not only diabetes but also of the clustering syndrome called "syndrome X" or "insulin resistance syndrome" which includes hypertension, dislipidemia and hypercoagulation. Therefore, TZD class of insulin sensitizers seem to have therapeutic potential to improve this clustering syndrome in addition to diabetes. Moreover, it was demonstrated that the TZD class of insulin sensitizers including troglitazone bind and activate the peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear hormone receptor. Although PPARgamma is predominantly expressed in adipose tissue, one of the target tissues for insulin, it have been subsequently found to be expressed in macrophages, vascular smooth muscle cells (VSMC), endothelial cells and several cancer cell lines. PPARgamma activation by PPARgamma agonists such as TZD class of insulin sensitizers in these cells modulates these cell functions such as the production of inflammatory cytokine by macrophages, proliferation and migration of VSMC, and growth or differentiation in cancer cells. In addition, troglitazone has potent antioxidant effect, and suppresses both L-type and receptor operated Ca2+ channel and protein kinase C. Thus since TZD class of insulin sensitizers has many kind of therapeutic effect in addition to lowering blood glucose, these agents expect to have therapeutic potential beyond diabetes.

Animals↗
PubMed2001

Toxic effect of troglitazone on cultured rat hepatocytes.

We examined the cytotoxicity of troglitazone toward cultured rat hepatocytes. The drug concentration- and time-dependently decreased cell viability and increased lactate dehydrogenase leakage from the cells. Troglitazone-induced cell death was characterized by "DNA ladders", condensation of nuclei, and a positive reaction to in situ nick-end labeling. The results indicate that troglitazone can cause apoptotic cell death in cultured rat hepatocytes.

Animals↗
PubMed1997

Troglitazone (CS-045) ameliorates albuminuria in streptozotocin-induced diabetic rats.

We studied the effect of troglitazone, a new oral antidiabetic agent that potentiates insulin action and reduces insulin resistance, on albuminuria in streptozotocin (STZ)-treated diabetic rats. Without affecting blood glucose level, blood pressure, and creatinine clearance, troglitazone treatment of diabetic rats significantly decreased the diabetes-associated albuminuria at all time points studied 14 to 12 weeks of treatment: diabetic 510 +/- 161 micrograms/24 h v diabetic treated 112 +/- 34 micrograms/24 h at 12 weeks, P < .05). These data suggest that troglitazone has potential in the treatment of diabetic nephropathy.

Albuminuria↗
PubMed2000

Subacute hepatic failure associated with a new antidiabetic agent, troglitazone: a case report with autopsy examination.

An autopsy case of fatal subacute hepatic failure after administration of troglitazone is described. The liver dysfunction developed about five months after the patient, a sixty-three-year-old woman, had been initially treated with troglitazone. The patient developed hepatic failure and died despite various hepatic auxiliary treatments such as plasmapheresis. Autopsy findings revealed focal liver cell necrosis, cholestasis and steatosis with infiltration of lymphocytes and neutrophils and lack of regenerative activity. The causative mechanism of liver dysfunction may be metabolite aberration, as a result of accumulation of hepatotoxic metabolite(s), in a category of idiosyncratic liver injury. It is proposed to monitor liver function strictly and periodically for the diabetic patients prescribed troglitazone.

Chromans↗
PubMed1999

The effect of insulin sensitizer, troglitazone, on lipoprotein lipase mass in preheparin serum.

Lipoprotein lipase mass exists in preheparin serum, even though the activity is scarcely found. The implication of this is unclear. We studied the effect of an insulin sensitizer, troglitazone, on this preheparin serum lipoprotein lipase mass (preheparin LPL mass) in non-insulin-dependent diabetes mellitus (NIDDM) patients as well as on serum lipid levels and low density lipoproteins (LDL) particle size. Thirty-one NIDDM patients with poor control were administered troglitazone 400 mg/day. Hemoglobin A1c had significantly decreased (13%, P < 0.001) 2 months later. Preheparin LPL mass had gradually increased and a 69% increase (P<0.01) was observed 4 months later. Triglyceride significantly decreased (23%, P < 0.01) and high density lipoprotein-cholesterol increased (10%, P < 0.01), whereas total cholesterol and LDL levels did not change 4 months later. The size of LDL increased significantly (P < 0.01). These results were consistent with the idea that preheparin LPL mass might be relating to the insulin sensitivity enhanced by troglitazone, as well as LDL particle size.

Adult↗
PubMedDate not supplied

Troglitazone-induced fulminant hepatitis: report of a case with autopsy findings.

Troglitazone is an insulin-sensitizing agent used to treat type 2 diabetes mellitus. Several cases have been reported of troglitazone-induced hepatic injury; some requiring transplantation, others resulting in death. We here present a case of troglitazone-induced fulminant hepatic necrosis that led to the death of the patient.

Aged↗
PubMed2006

Thiazolidinedione bioactivation: a comparison of the bioactivation potentials of troglitazone, rosiglitazone, and pioglitazone using stable isotope-labeled analogues and liquid chromatography tandem mass spectrometry.

Troglitazone, a thiazolidinedione (TZD) type insulin sensitizer for the treatment of diabetes, was withdrawn from the U.S. market after several fatal cases of hepatotoxicity. Although the mechanism(s) of these idiosyncratic adverse reactions are not completely understood, circumstantial evidence suggests at least a partial contribution of reactive metabolite formation. Despite isolated case reports of hepatotoxicity, the other TZD derivatives pioglitazone and rosiglitazone are comparatively safe. Herein, we report on the bioactivation potential of these drugs and their TZD ring isotope-labeled 2-(15)N-3,4,5-(13)C(3) analogues in rat and human liver microsomes supplemented with glutathione (GSH). Screening for GSH adducts as surrogate markers for reactive intermediate formation was performed by liquid chromatography tandem mass spectrometry. Chemical characterization of the GSH conjugates was conducted by acquisition of their respective product ion spectra and the comparison between unlabeled and stable isotope-labeled TZD derivatives. The data suggest that all drugs undergo bioactivation processes via a common metabolic activation on the TZD ring, yielding disulfide type GSH conjugates as evidenced by the loss of labeled positions in the TZD moiety. Additional bioactivation processes leading to GSH adducts not involving TZD ring scission were evident for troglitazone. In human liver microsomes at low substrate concentrations, only troglitazone yielded a predominant GSH adduct not involving TZD ring scission. This property may contribute, together with other factors such as the relatively high dose administered as well as its potential to induce hepatic cholestasis and oxidative stress, to the hepatotoxicity of this drug.

Animals↗
PubMed2004

Lack of efficacy of troglitazone at clinically achievable concentrations, with or without 9-cis retinoic acid or cytotoxic agents, for hepatocellular carcinoma cell lines.

Although the PPARgamma agonist troglitazone has been shown to induce growth inhibition of hepatocellular carcinoma (HCC) cells at high concentration, this study indicates troglitazone does not significantly inhibit the growth of HCC cells at clinically achievable concentrations (1-10 microM), and this lack of activity could not be improved by the addition of 9-cis-retinoic acid. Furthermore, no synergistic effect was found between troglitazone and cytotoxic anticancer agents.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

Renal protective effect of troglitazone in Wistar fatty rats.

Although it is known that renal injury develops in obesity and diabetes mellitus, there have been no investigations examining the impact of insulin resistance per se on the development of renal injury. The present study was undertaken to examine whether insulin resistance and obesity influence urinary protein excretion (UPE) in female heminephrectomized Wistar fatty rats (WFRs). After 24 weeks of heminephrectomy in WFRs, the body weight ([BW], 465+/-18 g; n = 6), blood pressure (155+/-5 mm Hg), serum insulin to glucose ratio (1.31+/-0.39 microU/mg), and daily UPE (24+/-7 mg/d) were greater versus Wistar lean rats ([WLRs] 258+/-8 g, 134+/-1 mm Hg, 0.19+/-0.06 microU/mg, and 5+/-1 mg/d, respectively; n = 6), whereas blood glucose levels did not increase significantly. In WFRs, long-term (ie, 24 weeks) treatment with troglitazone, an insulin-sensitizing agent, improved the serum insulin to glucose ratio (0.17+/-0.09 microU/mg), reduced blood pressure (to 140+/-4 mm Hg), and decreased UPE (to 7+/-1 mg/d), although it had no effect on BW. Of note, with troglitazone treatment, the reduction in proteinuria preceded the correction of hypertension (ie, at week 12). In conclusion, our study suggests that insulin resistance per se causes proteinuria that does not appear to depend on blood pressure. Furthermore, long-term therapy with troglitazone may be a useful tool for the treatment of renal injury in the insulin-resistant condition.

Animals↗
PubMed2002

Further insight on the hypoglycemic and nonhypoglycemic effects of troglitazone 400 or 600 mg/d: effects on the very-low-density and high-density lipoprotein particle distribution.

The effects of troglitazone 400 or 600 mg/d on the glycemic control, very-low-density lipoprotein (VLDL), and high-density lipoprotein (HDL) subclass concentrations and plasminogen-activator inhibitor 1 (PAI-1) levels were assessed in patients with type 2 diabetes that had not been controlled with dietary treatment. This was a multicenter, open-label, parallel-groups study. It included a run-in 4-week diet period and a 24-week randomized treatment. Fifty one patients received 400 mg/d and 55 patients 600 mg. The mean HbA(1c) concentration at the end of the study was similar for both doses. Troglitazone, regardless of dose, significantly improved insulin sensitivity assessed by the homeostasis model (HOMA). PAI-1 levels were significantly decreased in both groups by 13%. Higher HDL cholesterol concentrations and lower triglycerides levels were observed at the end of treatment. Triglyceride contents were reduced only in the lighter VLDL1. The change in HDL cholesterol concentration resulted from a combination of increased HDL3 cholesterol and lower HDL2 cholesterol levels. No differences were found in the effects of both treatment groups on the evaluated parameters. Our data provide new information about the actions of the drug on the lipid profile. Troglitazone reduces triglyceride levels by lowering the triglycerides content of the VLDL1 particles and increases HDL cholesterol concentrations by increasing HDL3 cholesterol levels.

Aged↗