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PubMed2000

Leptin, troglitazone, and the expression of sterol regulatory element binding proteins in liver and pancreatic islets.

Overaccumulation of lipids in nonadipose tissues of obese rodents may lead to lipotoxic complications such as diabetes. To assess the pathogenic role of the lipogenic transcription factor, sterol regulatory element binding protein 1 (SREBP-1), we measured its mRNA in liver and islets of obese, leptin-unresponsive fa/fa Zucker diabetic fatty rats. Hepatic SREBP-1 mRNA was 2.4 times higher than in lean +/+ controls, primarily because of increased SREBP-1c expression. mRNA of lipogenic enzymes ranged from 2.4- to 4.6-fold higher than lean controls, and triacylglycerol (TG) content was 5.4 times higher. In pancreatic islets of fa/fa rats, SREBP-1c was 3.4 times higher than in lean +/+ Zucker diabetic fatty rats. The increase of SREBP-1 in liver and islets of untreated fa/fa rats was blocked by 6 weeks of troglitazone therapy, and the diabetic phenotype was prevented. Up-regulation of SREBP-1 also occurred in livers of Sprague-Dawley rats with diet-induced obesity. Hyperleptinemia, induced in lean +/+ rats by adenovirus gene transfer, lowered hepatic SREBP-1c by 74% and the lipogenic enzymes from 35 to 59%. In conclusion, overnutrition increases and adenovirus-induced hyperleptinemia decreases SREBP-1c expression in liver and islets. SREBP-1 overexpression, which is prevented by troglitazone, may play a role in the ectopic lipogenesis and lipotoxicity complicating obesity in Zucker diabetic fatty rats.

Adenoviridae↗
PubMed2002

Rodent carcinogenicity with the thiazolidinedione antidiabetic agent troglitazone.

Carcinogenic potential of the thiazolidinedione antidiabetic troglitazone was assessed in 104-week studies in mice and rats. Mice were given 50, 400, or 800 mg/kg, male rats 100, 400, or 800 mg/kg, and female rats 25, 50, or 200 mg/kg. Vehicle and placebo controls were included. Survival was significantly decreased in both sexes of both species at high doses, but was adequate for valid evaluation of carcinogenicity. Hypertrophy and hyperplasia of brown adipose tissue was observed in both species at all doses, and fatty change and hypocellularity of bone marrow was noted in mice at all doses and in female rats at 50 and 200 mg/kg. Hepatocellular vacuolation was observed in mice at 400 and 800 mg/kg, and centrilobular hepatocellular hypertrophy occurred in rats at > or = 200 mg/kg. Ventricular dilatation, myocardial fibrosis, and atrial myocyte karyomegaly in male rats at 400 and 800 mg/kg and female rats at all doses were morphologically similar to spontaneous lesions, but incidence and severity were increased compared with controls. In mice, the incidence of hemangiosarcoma was increased in females at 400 mg/kg and in both sexes at 800 mg/kg. The incidence of hepatocellular carcinoma was increased in female mice at 800 mg/kg. Troglitazone exposure [AUC((0-24))] at the lowest dose associated with increased tumor incidence in mice was 16 times human therapeutic exposure at 400 mg daily. No tumors of any type were increased in rats at exposures up to 47 times therapeutic exposure.

Adipose Tissue, Brown↗
PubMed1996

A comparison of the hypotensive and hypoglycaemic actions of an angiotensin converting enzyme inhibitor, an AT1a antagonist and troglitazone.

OBJECTIVE: To define the relationship between changes in insulin sensitivity and attenuation of hypertension. METHODS: We investigated whether troglitazone (CS-045, an insulin sensitizer) has an antihypertensive effect in fructose (FRU)-fed Wistar rats with insulin resistance and simultaneously compared its hypotensive efficacy with those of alacepril (ALA, an angiotensin converting enzyme inhibitor) and TCV-116 (an AT1a receptor antagonist). Male rats aged 8 weeks were divided into five groups: controls fed normal chow, a FRU group fed FRU-rich (55%) chow, a FRU plus ALA group fed 30 mg/kg ALA per day, a FRU plus TCV-116 group fed 1 mg/kg TCV-116 per day and a FRU plus CS-045 group fed 70 mg/kg CS-045 per day). After 8 weeks, the body weight and systolic blood pressure were recorded and glucose tolerance was determined by glucose loading (2 g/kg, intraperitoneally) and a steady-state plasma glucose (SSPG) method. The plasma membrane glucose transporter 4 content in gastrocneumius muscle was determined by Western blot analysis. RESULTS: FRU increased blood pressure from 125 mmHg in controls to 141 mmHg (P < 0.01). ALA and TCV-116 administration decreased blood pressure to 111 and 107 mmHg, respectively (P < 0.01). CS-045 administration lowered blood pressure significantly to 121 mmHg. Area under the curve levels for plasma insulin during glucose loading increased from 1.7 in controls to 3.6 ng/ml x h in FRU-fed rats, but were lowered by the three drugs. SSPG levels increased from 12.5 in controls to 18.3 mmol/l in FRU-fed rats (P < 0.01), but were decreased by ALA and TCV-116 administration (P < 0.01). CS-045 administration also lowered SSPG levels to 15.3 mmol/l (P < 0.05). FRU-feeding induced a 1.24-fold increase in plasma membrane glucose transporter 4, which was not affected by ALA and TCV-116 administration, but was augmented 1.82-fold by CS-045 administration. Furthermore, the increased triglyceride level after FRU was diminished both by ALA and by CS-045 administration. CONCLUSION: These results suggest that, in the insulin-resistant state, troglitazone, an angiotensin converting enzyme inhibitor and an AT1a receptor antagonist show comparable hypotensive and hypoglycaemic effects.

Angiotensin Receptor Antagonists↗
PubMed2005

Troglitazone inhibits long-term glycation and oxidation of low-density lipoprotein.

Troglitazone (T) is a member of a new class of antidiabetic drugs termed thiazolidinediones (TZDs), which has previously been used as an anti-diabetic agent. In this study we investigated the influence of T, a ligand for PPAR-gamma receptor, on copper-catalyzed or cell-mediated oxidation of native, glycated, and glycoxidated low-density lipoprotein (LDL). A dose-dependent inhibition of copper-mediated low-density lipoprotein-oxidation, as monitored by the formation of oxidation-specific fluorescence, was observed for both native and glycated low-density lipoprotein. At the concentration of 20 microg/mL the inhibition amounted from 14.7% to 64.7% by all low-density lipoprotein forms. For glycated low-density lipoprotein we obtained the highest oxidation rate, but the most pronounced inhibition by T was found for glycoxidated low-density lipoprotein (goLDL). Inhibitory effects of T were also investigated by measurement of relative electrophoretic mobility (REM) in the concentration range of 0 to 20 microg/mL. The inhibition of 4h oxidation of native low-density lipoprotein was found in the entire concentration range, but significance was seen at 10 microg/mL. The long-term glycation and glycoxidation of low-density lipoprotein as measured by 5-hydroxymethyl-2-furaldehyde (5-HMF) formation and binding of fructosamine was found to be inhibited by T. In endothelial cell-mediated oxidation of low-density lipoprotein cytotoxicity of T in the concentration range of 0 to 160 microg/mL during 2 to 24 h oxidation was investigated. In the non-cytotoxic concentration range of 5 to 20 microg/mL, a significantly reduced liberation of isoprostane 8-epi-PGF2alpha during 24 h cell-mediated oxidation of low-density lipoprotein and its modifications was found. This inhibitory action of T was most significant in the case of goLDL and amounted to approximately 20% to 60% inhibition at 5 to 20 microg/mL T, respectively. In the concentration range of 40 to 160 microg/mL, however, T showed an increasing cytotoxic action, as evidenced by loss of cell adhesion, loss of cellular protein, morphological changes, and cell disintegration as well as by strongly enhanced troglitazone-mediated isoprostane 8-IP liberation (fivefold to sixfold). T may be used as a model to explore the thiazolidinediones' mechanism on oxidation in a more general aspect for treatment for T2DM, because T is not clinically available.

Adult↗
PubMed2004

Metabolic effects of Troglitazone in patients with diet-controlled type 2 diabetes.

BACKGROUND: In order to study the mechanisms of action of Troglitazone (TGZ) in vivo in Type 2 diabetes, its effects were studied on glucose metabolism, lipolysis and very low-density lipoprotein (VLDL) apolipoprotein B100 (apoB) kinetics. MATERIALS AND METHODS: A placebo-controlled, double-blind study was performed in 24 diet-treated patients randomized to receive TGZ 600 mg day(-1), TGZ 200 mg day(-1) or placebo for 8 weeks. Glucose and glycerol turnover were assessed after an overnight fast, and during sequential low-dose insulin infusions (0.01 U kg(-1) h(-1) followed by 0.015 U kg(-1) h(-1)) using 6,6-2H Glucose and 1,2,3-2H Glycerol. Very low-density lipoprotein apoB secretion was measured using l-13C-leucine, monitoring isotopic enrichment by gas chromatography-mass spectrometry. Treatment effects were analyzed by analysis of covariance, adjusting for baseline. RESULTS: Therapy resulted in a significant group differences in fasting plasma glucose adjusting for baseline (P=0.039). This was most evident at TGZ 600 mg daily [glucose decrease from (mean +/- SD) 9.2 +/- 2.7 to 6.6 +/- 0.9 mmol L(-1)]. HbA1c and insulin levels did not change significantly. Plasma nonesterified fatty acid (NEFA) levels decreased (P=0.045), most evidently at TGZ 200 mg daily, but glycerol was not significantly affected. Although no significant effects were observed on VLDL apoB or triglyceride concentrations, there were treatment differences in the absolute secretion rate of VLDL apoB of borderline (P=0.056) statistical significance, with a decrease observed at TGZ 600 mg daily [geometric mean, SD range, 0.94 (0.41-2.15) to 0.40 (0.14-1.13 mg kg(-1) h(-1))]. Very low-density lipoprotein apoB fractional secretion rate and pool size were unaffected. The VLDL triglyceride: apoB molar ratio differed between treatment groups (P=0.013), being higher in the TGZ 600 mg group [5714 (4128-7741) to 8092 (5669-11552)]. Neither glucose nor glycerol rates of appearance were significantly altered by TGZ and nor did TGZ affect their suppression by insulin. DISCUSSION: The PPARgamma agonist, troglitazone, decreases fasting glucose and NEFA levels in diet-treated Type 2 diabetes. It may also decrease VLDL particle secretion. These effects would be considered beneficial. The biological importance of the increase in VLDL-triglyceride enrichment warrants further study.

Apolipoprotein B-100↗
PubMed2000

Hepatotoxicity due to troglitazone: report of two cases and review of adverse events reported to the United States Food and Drug Administration.

Two patients (a 48-year-old woman and a 62-year-old man) developed clinical and laboratory signs of hepatotoxicity due to troglitazone (Rezulin), a thiazolidinedione used in treatment of diabetes mellitus. There was no clear clinical evidence of drug allergy, although the woman experienced colitis before the onset of recognized hepatotoxicity. Liver biopsies showed bridging necrosis and fibrosis in the woman and hepatitis with granuloma formation in the man. The abnormalities in liver chemistries resolved promptly upon cessation of the drug. Cases involving 46 patients reported to the United States Food and Drug Administration are also reviewed. Troglitazone is a useful new oral antihyperglycemic agent, but in about 1.9% of patients hepatotoxicity has occurred, which may be severe and even fatal. Frequent monitoring of serum liver chemistries in patients taking the drug is essential.

Chromans↗
PubMed2005

The synthetic PPARgamma agonist troglitazone inhibits IL-5-induced CD69 upregulation and eosinophil-derived neurotoxin release from eosinophils.

Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a nuclear receptor that regulates lipid metabolism. Recently, PPARgamma was reported to be a negative regulator in the immune system. Eosinophils also express PPARgamma, however, the role of PPARgamma in eosinophil functions is not well understood. Surface expression of CD69 and eosinophil-derived neurotoxin (EDN) release are well-known activation markers of eosinophils. We investigated the effect of a PPARgamma agonist on human eosinophil functions such as IL-5-induced CD69 surface expression and EDN release. IL-5 significantly induced eosinophil CD69 surface expression analyzed using flow cytometry and EDN release measured by ELISA. IL-5-induced eosinophil CD69 surface expression and EDN release were significantly inhibited by the synthetic PPARgamma agonist troglitazone, and these effects were reversed by a PPARgamma antagonist. The PPARgamma agonist troglitazone has a potent inhibitory effect on activation and degranulation of eosinophils, and it may be a therapeutic modality for the treatment of allergic diseases.

Analysis of Variance↗
PubMed1997

Leptin- or troglitazone-induced lipopenia protects islets from interleukin 1beta cytotoxicity.

Interleukin 1beta (IL-1beta)-induced beta cell cytotoxicity has been implicated in the autoimmune cytotoxicity of insulin-dependent diabetes mellitus. These cytotoxic effects may be mediated by nitric oxide (NO). Since long-chain fatty acids (FFA), like IL-1beta, upregulate inducible nitric oxide synthase and enhance NO generation in islets, it seemed possible that islets might be protected from IL-1beta-induced damage by lowering their lipid content. We found that IL-1beta-induced NO production varied directly and islet cell viability inversely with islet triglyceride (TG) content. Fat-laden islets of obese rats were most vulnerable to IL-1beta, while moderately fat-depleted islets of food-restricted normal rats were less vulnerable than those of free-feeding normal rats. Severely lipopenic islets of rats made chronically hyperleptinemic by adenoviral leptin gene transfer resisted IL-1beta cytotoxicity even at 300 pg/ml, the maximal concentration. Troglitazone lowered islet TG in cultured islets from both normal rats and obese, leptin-resistant rats and reduced NO production and enhanced cell survival. We conclude that measures that lower islet TG content protect against IL-1beta-induced NO production and cytotoxicity. Leptin or troglitazone could provide in vivo protection against insulin-dependent diabetes mellitus.

Animals↗
PubMed1998

Troglitazone (CS-045) inhibits beta-cell proliferation rate following stimulation of insulin secretion in HIT-T 15 cells.

Thiazolidinedione analogs are new antidiabetic agents that attenuate peripheral insulin resistance in noninsulin-dependent diabetic patients; however, the effects of these agents on insulin secretion are not known. We determined the short-term and long-term effects of troglitazone (CS-045) on insulin secretion in a Syrian hamster clonal beta-cell line, HIT-T 15 cells. The direct effect of troglitazone (CS-045: 10(-6)-10(-4) M) on insulin secretion was examined in F-12 K incubation medium containing 7 mM glucose. CS-045 significantly stimulated insulin secretion within 10 min at the concentration of 10(-4) M and dose dependently stimulated insulin secretion within 60 min at the concentration of 10(-6)-10(-4) M. The addition of 10(-5) M CS-045 showed an immediate increase of cytoplasmic free Ca2+ concentrations ([Ca2+]i). Removal of extracellular Ca2+ by the addition of 1.5 mM EGTA completely abolished the 10(-4) M CS-045-induced insulin secretion for 10-min. Long-term incubation (24 h) with 10(-4) M CS-045 significantly decreased beta-cell insulin content and inhibited insulin secretion. During a 5-day incubation, CS-045 showed a dose-dependent reduction of insulin secretion measured during the final 24 h. Long-term incubation with CS-045 over 3 days inhibited the beta-cell proliferation rate, assessed with [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] (MTT) assay. CS-045 dose dependently increased the amount of DNA fragmentation measured by ELISA. The addition of nifedipine failed to attenuate the reduction of beta-cell proliferation rate and insulin secretion by CS-045, nifedipine antagonized an increase in the amount of DNA fragmentation caused by 10(-4) M CS-045. The present studies provide evidence that CS-045 inhibits beta-cell function following an acute stimulation of insulin secretion in HIT-T 15 cells. The immediate stimulation of insulin secretion by CS-045 may be mediated by an increase in Ca2+ influx from extracellular space. The induction of apoptosis may partially involves the reduction of beta-cell number by CS-045.

Animals↗
PubMed2000

Dehydroepiandrosterone suppresses elevated hepatic glucose-6-phosphatase mRNA level in C57BL/KsJ-db/db mice: comparison with troglitazone.

Dehydroepiandrosterone (DHEA) is known to improve hyperglycemia of diabetic C57BL/KsJ-db/db mice that are obese and insulin resistant. In a previous study, we reported that DHEA as well as troglitazone suppresses the elevated hepatic gluconeogenic enzymes, glucose-6-phosphatase (G6Pase) and fructose-1,6-bisphosphatase (FBPase) activities in C57BL/KsJ-db/db mice. In the present study, we evaluated the changes in mRNA of G6Pase and FBPase in db/db mice. Despite hyperinsulinemia, the G6Pase mRNA level of db/db mice was elevated as compared to their heterozygote littermate db/+m mice. In contrast, the FBPase mRNA level was not elevated in db/db mice. Administration of DHEA for two weeks significantly decreased the blood glucose level and the elevated G6Pase mRNA level in db/db mice. No significant changes were seen in the FBPase mRNA level after the administration of DHEA. Administration of troglitazone also decreased the blood glucose and G6Pase mRNA level in db/db mice although no changes were seen in the FBPase mRNA level. These results suggest that the elevation of G6Pase mRNA is important in elucidating the cause of insulin resistance, and that the G6Pase gene is at least one target for the hypoglycemic effects of DHEA as an insulin sensitizing agent in db/db mice.

Animals↗
PubMed2000

Impaired expression of the uncoupling protein-3 gene in skeletal muscle during lactation: fibrates and troglitazone reverse lactation-induced downregulation of the uncoupling protein-3 gene.

The expression of uncoupling protein (UCP)-3 mRNA in skeletal muscle is dramatically reduced during lactation in mice. The reduction in UCP-3 mRNA levels lowers the amount of the UCP-3 protein in skeletal muscle mitochondria during lactation. Spontaneous or abrupt weaning reverses the downregulation of the UCP-3 mRNA but not the reduction in UCP-3 protein levels. In lactating and virgin mice, however, fasting increases UCP-3 mRNA levels. Changes in UCP-3 mRNA occur in parallel with modifications in the levels of free fatty acids, which are reduced in lactation and are upregulated due to weaning or fasting. Modifications in the energy nutritional stress of lactating dams achieved by manipulating litter sizes do not influence UCP-3 mRNA levels in skeletal muscle. Conversely, when mice are fed a high-fat diet after parturition, the downregulation of UCP-3 mRNA and UCP-3 protein levels due to lactation is partially reversed, as is the reduction in serum free fatty acid levels. Treatment of lactating mice with a single injection of bezafibrate, an activator of the peroxisome proliferator-activated receptor (PPAR), raises UCP-3 mRNA in skeletal muscle to levels similar to those in virgin mice. 4-chloro-6-[(2,3-xylidine)-pirimidinylthio] acetic acid (WY-14,643), a specific ligand of the PPAR-alpha subtype, causes the most dramatic increase in UCP-3 mRNA, whereas troglitazone, a specific activator of PPAR-gamma, also significantly increases UCP-3 mRNA abundance in skeletal muscle of lactating mice. However, in virgin mice, bezafibrate and WY-14,643 do not significantly affect UCP-3 mRNA expression, whereas troglitazone is at least as effective as it is in lactating dams. It is proposed that the UCP-3 gene is regulated in skeletal muscle during lactation in response to changes in circulating free fatty acids by mechanisms involving activation of PPARs. The impaired expression of the UCP-3 gene is consistent with the involvement of UCP-3 gene regulation in the reduction of the use of fatty acids as fuel by the skeletal muscle and in impaired adaptative thermogenesis, both of which are major metabolic adaptations that occur during lactation.

Animals↗
PubMed2001

Troglitazone induces GLUT4 translocation in L6 myotubes.

A number of studies have demonstrated that insulin resistance in the skeletal muscle plays a pivotal role in the insulin resistance associated with obesity and type 2 diabetes. A decrease in GLUT4 translocation from the intracellular pool to the plasma membranes in skeletal muscles has been implicated as a possible cause of insulin resistance. Herein, we examined the effects of an insulin-sensitizing drug, troglitazone (TGZ), on glucose uptake and the translocation of GLUT4 in L6 myotubes. The prolonged exposure (24 h) of L6 myotubes to TGZ (10(-5) mol/l) caused a substantial increase in the 2-deoxy-[3H]D-glucose (2-DG) uptake without changing the total amount of the glucose transporters GLUT4, GLUT1, and GLUT3. The TGZ-induced 2-DG uptake was completely abolished by cytochalasin-B (10 micromol/l). The ability of TGZ to translocate GLUT4 from light microsomes to the crude plasma membranes was greater than that of insulin. Both cycloheximide treatment (3.5 x 10(-6) mol/l) and the removal of TGZ by washing reversed the 2-DG uptake to the basal level. Moreover, insulin did not enhance the TGZ-induced 2-DG uptake additively. The TGZ-induced 2-DG uptake was only partially reversed by wortmannin to 80%, and TGZ did not change the expression and the phosphorylation of protein kinase B; the expression of protein kinase C (PKC)-lambda, PKC-beta2, and PKC-zeta; or 5'AMP-activated protein kinase activity. a-Tocopherol, which has a molecular structure similar to that of TGZ, did not increase 2-DG uptake. We conclude that the glucose transport in L6 myotubes exposed to TGZ for 24 h is the result of an increased translocation of GLUT4. The present results imply that the effects of troglitazone on GLUT4 translocation may include a new mechanism for improving glucose transport in skeletal muscle.

Animals↗
PubMed2000

[Troglitazone for treatment of polycystic ovary syndrome].

Polycystic ovary syndrome(PCOS) is characterized by clinical symptoms such as menstrual dysfunction, unovulatory infertility, masculinization, obesity, polycystic ovary by ultrasound, and endocrine abnormalities such as hyperandrogenism, and elevated LH to FSH ratio. Recent reports suggest that insulin resistance plays an important role in the pathogenesis of PCOS, and several insulin sensitizing agents have been used for the treatment of PCOS. Troglitazone, one of the thiazolidinediones, improves not only insulin sensitivity but also hyperandrogenism and ovulatory function. Troglitazone appears to be useful in treating women with PCOS. Further investigations are needed to assess the effectiveness and safety.

Chromans↗
PubMed2003

Troglitazone reduces heat shock protein 70 content in primary rat hepatocytes by a ubiquitin proteasome independent mechanism.

Troglitazone (TRG) is an antidiabetic agent that increases the insulin sensitivity of target tissues in non-insulin-dependent diabetes mellitus. Therapy with troglitazone has been associated with severe hepatic injury in a small percentage of patients and the mechanism of TRG-induced hepatotoxicity remains unclear. A family of highly conserved stress proteins identified as heat shock proteins (Hsps), are well-known to protect cells against a wide variety of toxic conditions such as extreme temperature changes, oxidative stress and toxic drugs. The stress-inducible Hsp 70 protein is one of the best-known endogenous factors protecting cells from injury under various stress conditions. Here we examined the effects of TRG on Hsp 70 mRNA and protein expression in primary cultures of rat hepatocytes. We also investigated the effects of TRG in an in vivo model by examining Hsp 70 protein levels in livers prepared from C57 mice fed a 0.2% dietary admixture of TRG. Levels of Hsp 70 mRNA increased in a concentration-dependent manner in rat hepatocytes treated for 8h with increasing concentrations of TRG. However, Hsp 70 protein levels decreased significantly in cells treated with increasing concentrations of TRG. C57 mice fed a 0.2% admixture of TRG for 10 days, also demonstrated decreased liver Hsp 70 protein levels. To investigate whether TRG decreased Hsp 70 protein levels by activating the ubiquitin-proteasome pathway, cells were pretreated with 10 microM lactacystin, a potent and specific inhibitor of this pathway. Lactacystin pretreatment failed to prevent TRG-induced decrease in Hsp 70 protein. The data suggests that TRG-induced effects may be mediated through another system of regulated proteolysis or may involve a post-transcriptional regulator mechanism. The mechanism of TRG-induced hepatotoxicity remains unclear, however, the effects induced by TRG on Hsp 70 may, in part, play a role.

Acetylcysteine↗
PubMed2006

[Effects of peroxisome proliferator-activated receptor-gamma ligand troglitazone on colon cancer cell growth].

OBJECTIVE: To investigate the expression of peroxisome proliferator-activated receptor-gamma (PPARgamma) in colon cancer cell lines and the effects of PPARgamma activation by its ligand troglitazone on cell growth in SW-480 cells. METHODS: PPARgamma expression was detected in Lovo, HT-29 and SW-480 cells using western blot. The effects of PPARgamma activation by its ligand troglitazone (TGZ) and selective antagonist T0070907 on cell growth were assessed by MTT and cell count methods; apoptosis was detected by flow cytometry method. RESULTS: Western blot result revealed that PPARgamma protein was highly expressed in Lovo and HT-29 cells and there was relatively lower expression in SW-480 cells. Cell count method and MTT revealed that activation of SW-480 cells with TGZ resulted in inhibition of growth in a dose dependent manner. The effect of anti-proliferation increased with increasing doses of TGZ. Rates of growth inhibition were 3.3%, 8.3%, 25%, and 29% for different doses 5, 10, 20 and 25 micromol/L respectively. Flow cytometry method detected apoptosis in a dose-dependent manner. When the concentration of TGZ was less than 15 micromol/L , the apoptotic effect was found to be weak. The apoptotic effect was prominent when the concentration exceeded 20 micromol/L. Cell count method revealed that selective antagonist of PPARgamma stimulated cell growth of SW-480 cells in a dose dependent manner. CONCLUSION: PPARgamma is expressed in colon cancer cells. Activation of PPARgamma by its ligands in colon cells has potent anti-proliferative and pro-apoptotic effects, suggesting that PPARgamma activation by its ligands may provide therapeutic value for colorectal cancer patients.

Antineoplastic Agents↗
PubMed1996

Prediction of the human pharmacokinetics of troglitazone, a new and extensively metabolized antidiabetic agent, after oral administration, with an animal scale-up approach.

We have attempted to predict the human pharmacokinetics of troglitazone after oral administration based on animal data. Troglitazone is a new antidiabetic agent that exhibits a high-metabolic clearance and is metabolized mainly in the liver to sulfate and glucuronide conjugates. The prediction of the area under the plasma concentration-time curve (AUCp.o.) and bio-availability (F) in humans after oral administration was initially attempted by use of allometric equations involving the oral plasma clearance of total (CLp.o.) or unbound drug (CLp.o.,fu), or the hepatic intrinsic clearance of unbound drug (CLuint) and animal body weight. The exponents in the allometric equations between the clearances and body weights were 0.63 to 0.82 with high correlation coefficients (r > .98), and there was no marked difference in predictability by the three methods. Next, the prediction of the range of plasma profiles after oral administration to humans was attempted by the following series of steps: (1) calculation of the exponent and coefficients in the allometric relationships between body weight and parameters, such as total body plasma clearance (CLi.v.) and various distribution volumes (Vss, V beta and Vc) based on animal data; (2) estimation of the absorption rate constant (ka) from allometric relationship to body weight, and estimation of F value from the predicted AUCp.o. (3) description of the plasma concentration-time profiles after oral administration by an equation involving the allometric exponents and coefficients, ka, F and body weight. The observed and simulated plasma profiles were similar and the predicted AUCp.o. values were 60 to 120% of those observed. These methodologies will be useful for predicting the human pharmacokinetics after oral dosing from animal data.

Administration, Oral↗
PubMed1997

Pharmacokinetics of troglitazone, an antidiabetic agent: prediction of in vivo stereoselective sulfation and glucuronidation from in vitro data.

Sulfation and glucuronidation, the major routes of metabolism of troglitazone, an antidiabetic agent, were examined in vitro using hepatic cytosol and microsomes prepared from KK mice, an animal model of non-insulin-dependent diabetes mellitus. Stereoselectivity was observed for both conjugation reactions, and the metabolic intrinsic clearance of glucuronidation was about 3- to 100-fold higher than that of sulfation for each stereoisomer. In addition, the metabolic intrinsic clearance of glucuronidation exhibited an 8-fold difference among stereoisomers. The predicted metabolic clearance for each stereoisomer, calculated from the in vitro data based on a dispersion model, was comparable to the measured metabolic clearance in vivo, ranging from 27 to 93%. We also attempted to predict the in vivo metabolic clearance from in vitro metabolism data, to investigate species differences in the stereoselectivity of the conjugation reactions in normal animals, i.e., ddY mice and rats. For ddY mice the in vivo hepatic glucuronidation clearance was 170-fold higher than the corresponding sulfation clearance, whereas for rats the sulfation clearance was 6-fold higher than the glucuronidation clearance. The hepatic sulfation clearance in mice and rats predicted from in vitro metabolism data was 5.3- and 1.1-fold higher, respectively, than that in vivo, calculated from the plasma disposition of parent drug and biliary excretion of metabolites. For glucuronidation, the predicted values in mice and rats were 1.0- and 0.33-fold higher, respectively. These results suggest that semiquantitative extrapolation of in vitro stereoselective metabolism of troglitazone, by conjugation, to the in vivo situation is possible.

Animals↗
PubMedDate not supplied

The role of troglitazone in treating the insulin resistance syndrome.

Insulin resistance is characterized by impaired responsiveness to endogenous or exogenous insulin and often results in the insulin resistance syndrome, a clustering of cardiovascular risk factors that includes abdominal obesity, hypertension, dyslipidemia, glucose intolerance, and hyperinsulinemia. Although the mechanism responsible for insulin resistance has not been completely defined, it is likely due to defective insulin receptor signaling and results in decreased use of glucose. Troglitazone, the first in a new class of drugs, directly decreases insulin resistance by improving insulin-mediated glucose disposal and reduces plasma insulin concentrations. Glycemic control achieved with troglitazone monotherapy is equivalent to that with sulfonylurea and metformin, and when combined with these agents offers additional plasma glucose reduction. Studies are necessary to determine the effect of thiazolidinediones on morbidity and mortality of patients with type 2 diabetes and insulin resistance.

Chromans↗