Hypoglycemic agent YM440 suppresses hepatic glucose output via gluconeogenesis by reducing glucose-6-phosphatase activity in obese Zucker rats

Using a glucose clamp, we had shown that YM440, (Z)-1,4-bis{4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy}but-2-ene, reduced the increased hepatic glucose output in obese Zucker rats. We further examined effects of YM440 on ¹⁴C-incorporation from [¹⁴C]bicarbonate into blood glucose via gluconeogenesis, and on gluconeogenic enzymatic activities. Fed obese Zucker rats showed a 4-fold increase of ¹⁴C-incorporation into blood glucose compared to that in lean rats. Glucose-6-phosphatase and fructose-1,6-bisphosphatase activities in obese rats were increased 1.4-fold and 1.6-fold compared with lean rats. YM440 (300 mg/kg for 2 weeks) decreased ¹⁴C-incorporation into blood glucose by 29% in obese rats. Glucose-6-phosphatase but not fructose-1,6-bisphosphatase activity was reduced by YM440 and closely correlated with ¹⁴C-incorporation into blood glucose, indicating a key role for glucose-6-phosphatase in hepatic glucose output. These results suggest that the increased gluconeogenesis in obese rats is mainly due to the increased activities of glucose-6-phosphatase and fructose-1,6-bisphosphatase and that YM440 suppresses hepatic glucose output by reducing glucose-6-phosphatase activity.     

Antihyperglycaemic effect of Casearia esculenta root extracts in streptozotocin-induced diabetic rats

The present study was carried out to evaluate the antihyperglycaemic effect of Casearia esculenta root extract and to study the activities of liver hexokinase and gluconeogenic enzymes such as glucose-6-phosphatase and fructose-1,6-bisphosphatase in liver and kidney of normal and streptozotocin-induced diabetic rats. Oral administration of aqueous extract of root (300 mg/kg body weight) for 45 days resulted in a significant reduction in blood glucose from 250.79 +/- 12.65 to 135.70 +/- 8.90 and in a decrease in the activities of glucose-6-phosphatase and fructose-1,6-bishosphatase and an increase in the activity of liver hexokinase. However, in the case of 200 mg/kg body weight of extract, less activity was observed. The study clearly shows that the root extract of C. esculenta possesses potent antihyperglycaemic activity but weaker than that of glibenclamide.     

Effect of Pterocarpus santalinus bark,on blood glucose,serum lipids,plasma insulin and hepatic carbohydrate metabolic enzymes in streptozotocin-induced diabetic rats

Aim of the study

The present study was designed to investigate the effect of bark of Pterocarpus santalinus, an ethnomedicinal plant, on blood glucose, plasma insulin, serum lipids and the activities of hepatic glucose metabolizing enzymes in streptozotocin-induced diabetic rats.

Materials and methods

Streptozotocin-induced diabetic rats were treated (acute/short-term and long-term) with ethyl acetate:methanol fractions of ethanolic extract of the bark of P. santalinus. Fasting blood glucose, HbA_1C, plasma insulin and protein were estimated before and after the treatment, along with hepatic glycogen, and activities of hexokinase, glucose-6-phosphatase, fructose-1,6-bisphosphatase and glucose-6-phosphate dehydrogenase. Further anti-hyperlipidemic activity was studied by measuring the levels of serum lipids and lipoproteins.

Results

Phytochemical analysis of active fraction showed the presence of flavonoids, glycosides and phenols. Biological testing of the active fraction demonstrated a significant antidiabetic activity by reducing the elevated blood glucose levels and glycosylated hemoglobin, improving hyperlipidemia and restoring the insulin levels in treated experimental induced diabetic rats. Further elucidation of mechanism of action showed improvement in the hepatic carbohydrate metabolizing enzymes after the treatment. Our present investigation suggests that active fraction of ethanolic extract of bark of P. santalinus decreases streptozotocin induced hyperglycemia by increasing glycolysis and decreasing gluconeogenesis.     

Antidiabetic activity of Momordica charantia seeds on streptozotocin induced diabetic rats

The present study was aimed to evaluate the hypoglycemic efficacy in an aqueous extract of seeds of two varieties, namely a country and a hybrid variety of Momordica charantia (MCSEt1 and MCSEt2) respectively in streptozotocin (STZ) induced diabetic rats. STZ-induced diabetic rats were treated with aqueous extracts of MCSEt1 and t2 for a period of 30 days. MCSEt1 and t2 extract treatment to diabetic rats resulted in a significant reduction in blood glucose, glycosylated hemoglobin, lactate dehydrogenase, glucose-6-phosphatase, fructose-1,6-bisphosphatase and glycogen phosphorylase, and a concomitant increase in the levels of hemoglobin, glycogen and activities of hexokinase and glycogen synthase. These results clearly show the antidiabetic properties of Momordica charantia. Both the varieties showed safe and significant hypoglycemic effects which were more pronounced in MCSEt1 compared to MCSEt2 and glibenclamide.     

Effect of Coccinia indica on Blood Glucose,Insulin and Key Hepatic Enzymes in Experimental Diabetes

Administration of Coccinia indica leaf extract to normal and streptozotocin diabetic animals exhibited significant hypoglycemic and antihyperglycemic effect and reversed biochemical complications. Oral administration of 200mg/ kg of ethanol extract of Coccinia indica leaves (CLEt) to diabetic animals for 45 days resulted in a significant reduction in blood glucose, glycosylated haemoglobin and an increase in total haemoglobin and plasma insulin. Similarly, the administration of CLEt to normal animals resulted in a significant hypoglycemic effect. The activities of hepatic hexokinase, glucose-6-phosphatase, fructose-1,6-bisphosphatase and glucose-6-phosphate dehydrogenase, a lipogenic enzyme, were measured in the liver of normal, diabetic, normal rats separately treated with CLEt and glibenclamide, and diabetic rats treated separately with CLEt and glibenclamide. The activities of the lipogenic enzyme and hexokinase were significantly decreased, whereas the activities of gluconeogenic enzymes were significantly increased in the diabetic liver. Both CLEt and glibenclamide were able to restore the altered enzyme activities to almost control levels. CLEt was more effective than glibenclamide. The results indicate that the administration of CLEt to diabetic animals normalizes blood glucose and causes marked improvement of altered carbohydrate metabolic enzymes during diabetes.     

Effect of tetrahydrocurcumin on blood glucose, plasma insulin and hepatic key enzymes in streptozotocin induced diabetic rats

The enzymes of glucose and lipid metabolism are markedly altered in experimental diabetes. In the present study, we investigated the effect of tetrahydrocurcumin (THC), one of the active metabolites in curcumin, on the key hepatic metabolic enzymes involved in carbohydrate metabolism in streptozotocin-induced diabetic rats. Different doses of THC (20, 40, and 80 mg\kg body weight) were orally administered to diabetic rats for 45 days. The activities of hexokinase, glucose-6-phosphate dehydrogenase (G6PD), glucose-6-phosphatase, fructose-1,6-bisphosphatase, and sorbitol dehydrogenase in liver, and glycogen content in liver and muscle were assayed. In untreated diabetic control rats, the activities of the gluconeogenic enzymes were significantly increased, whereas hexokinase and G6PD activity and glycogen levels were significantly decreased. Both THC and curcumin were able to restore the altered enzyme activities to near normal levels. Tetrahydrocurcumin was more effective than curcumin. Our results indicate that the administration of THC to diabetic animals normalizes blood glucose and causes a marked improvement of altered carbohydrate metabolic enzymes.     

Modulatory effects of fisetin, a bioflavonoid, on hyperglycemia by attenuating the key enzymes of carbohydrate metabolism in hepatic and renal tissues in streptozotocin-induced diabetic rats

Fisetin (3, 7, 3′, 4′-tetrahydroxyflavone) is a bioflavonoid found in fruits and vegetables. It exhibits a wide variety of pharmacological properties, including antioxidant, antiinflammatory and anticarcinogenic effects. Recently we have reported the hypoglycemic actions of fisetin. Oral administration of fisetin (10 mg/kg body weight) to diabetic rats for 30 days established a significant (P < 0.05) decline in blood glucose and glycosylated hemoglobin levels and a significant (P < 0.05) increase in plasma insulin level. In the present study the activities of key enzymes of carbohydrate metabolism were assayed to establish the modulatory actions of fisetin in maintaining the glucose homeostasis. The altered activities of key enzymes of carbohydrate metabolism such as hexokinase, pyruvate kinase, lactate dehydrogenase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, glucose-6-phosphate dehydrogenase, glycogen synthase and glycogen phosphorylase in liver and kidney tissues of diabetic rats were significantly (P < 0.05) reverted to near normalcy by the administration of fisetin. Thus, fisetin regulates carbohydrate metabolism by modulating the key regulatory enzymes in the hepatic and renal tissues of diabetic rats.     

Protective effect of bioflavonoid myricetin enhances carbohydrate metabolic enzymes and insulin signaling molecules in streptozotocin–cadmium induced diabetic nephrotoxic rats

Diabetic nephropathy is the kidney disease that occurs as a result of diabetes. The present study was aimed to evaluate the therapeutic potential of myricetin by assaying the activities of key enzymes of carbohydrate metabolism, insulin signaling molecules and renal function markers in streptozotocin (STZ)–cadmium (Cd) induced diabetic nephrotoxic rats. After myricetin treatment schedule, blood and tissue samples were collected to determine plasma glucose, insulin, hemoglobin, glycosylated hemoglobin and renal function markers, carbohydrate metabolic enzymes in the liver and insulin signaling molecules in the pancreas and skeletal muscle. A significant increase of plasma glucose, glycosylated hemoglobin, urea, uric acid, creatinine, blood urea nitrogen (BUN), urinary albumin, glycogen phosphorylase, glucose-6-phosphatase, and fructose-1,6-bisphosphatase and a significant decrease of plasma insulin, hemoglobin, hexokinase, glucose-6-phosphate dehydrogenase, glycogen and glycogen synthase with insulin signaling molecule expression were found in the STZ–Cd induced diabetic nephrotoxic rats. The administration of myricetin significantly normalizes the carbohydrate metabolic products like glucose, glycated hemoglobin, glycogen phosphorylase and gluconeogenic enzymes and renal function markers with increase insulin, glycogen, glycogen synthase and insulin signaling molecule expression like glucose transporter-2 (GLUT-2), glucose transporter-4 (GLUT-4), insulin receptor-1 (IRS-1), insulin receptor-2 (IRS-2) and protein kinase B (PKB). Based on the data, the protective effect of myricetin was confirmed by its histological annotation of the pancreas, liver and kidney tissues. These findings suggest that myricetin improved carbohydrate metabolism which subsequently enhances glucose utilization and renal function in STZ–Cd induced diabetic nephrotoxic rats.     

Effect of an aqueous extract of Phaseolus vulgaris on plasma insulin and hepatic key enzymes of glucose metabolism in experimental diabetes

Oral administration of 200 mg/kg of aqueous extract of Phaseolus vulgaris pods (PPEt) to diabetic animals for 45 days resulted in a significant decrease in blood glucose, glycosylated haemoglobin and significant increase in total haemoglobin and plasma insulin. Similarly oral administration of PPEt to normal animals resulted in a significant hypoglycemic effect. The activities of hepatic hexokinase, glucose 6-phosphatase, fructose-1,6-bisphosphatase and glucose-6-phosphate dehydrogenase, a lipogenic enzyme, were measured in the liver of normal and experimental animals. The activities of the lipogenic enzyme and hexokinase were significantly decreased, whereas the activities of gluconeogenic enzymes were significantly increased in the diabetic liver. Both PPEt and glibenclamide reversed the activities of these enzymes to near normal levels. PPEt was more effective than glibenclamide. The results indicate that the administration of PPEt to diabetic animals normalizes blood glucose and causes a marked improvement of altered carbohydrate metabolic enzymes during diabetes.     

Antidiabetic activity of alcoholic stem extract of Gymnema montanum in streptozotocin-induced diabetic rats

In the present study, the effect of alcoholic stem extract of Gymnema montanum (GMSt) on blood glucose, plasma insulin, and carbohydrate metabolic enzymes were studied in experimental diabetes. Diabetes mellitus was induced by a single intraperitoneal injection of STZ (60 mg/kg bw). Five days after STZ induction, diabetic rats received GMSt orally at the doses of 25, 50, 100 and 200 mg/kg daily for 3 weeks. Graded doses of stem extract showed a significant reduction in blood glucose levels and improvement in plasma insulin levels. The effect was more pronounced in 100 and 200 mg/kg than 50 mg/kg. GMSt showed significant increase in hexokinase, Glucose-6-phosphate dehydrogenase and glycogen content in liver of diabetic rats while there was significant reduction in the levels of glucose-6-phosphatase and fructose-1,6-bisphosphatase. The present study clearly indicated significant antidiabetic effect with the stem extract of G. montanum and lends support for its traditional usage.     

Biochemical evaluation of antidiabetogenic properties of some commonly used Indian plants on streptozotocin-induced diabetes in experimental rats

1. Diabetes mellitus is a serious metabolic disorder with micro- and macrovascular complications that results in significant morbidity and mortality. 2. The aim of the present study was to evaluate the hypoglycaemic efficacy of commonly used traditional Indian plants, such as Murraya koenigii, Mentha piperitae, Ocimum sanctum and Aegle marmelos, in streptozotocin (STZ)-induced experimental rats. 3. Oral administration of the ethanolic extract of these plants resulted in a significant decrease in the levels of blood glucose, glycosylated haemoglobin and urea, with a concomitant increase in glycogen, haemoglobin and protein, in diabetic rats. Treatment with these plant extracts also resulted in an increase in insulin and C-peptide levels and glucose tolerance. 4. The decreased activities of carbohydrate-metabolising enzymes, such as hexokinase, glucose-6-phosphate dehydrogenase and glycogen synthase, in diabetic rats were significantly elevated towards near normal in rats treated with extracts of M. koenigii, O. sanctum and A. marmelos; the increased activities of lactate dehydrogenase, fructose-1,6-bisphosphatase, glucose-6-phosphatase and glycogen phosphorylase in STZ diabetic rats were significantly reduced following treatment with the plant extracts. 5. Elevated specific binding of [(125)I]-labelled insulin to the receptor found in diabetic rats was markedly decreased in extract-treated groups. However, treatment of diabetic rats with M. piperitae did not result in any significant modification in all parameters. 6. Phytochemical screening conducted by us revealed the presence of biologically active ingredients in the ethanolic extracts of M. koenigii, O. sanctum and A. marmelos, which may readily account for the observed hypoglycaemic activity.     

Modulatory effects of morin on hyperglycemia by attenuating the hepatic key enzymes of carbohydrate metabolism and β-cell function in streptozotocin-induced diabetic rats

The present study was aimed to evaluate the effect of morin on blood glucose, insulin level, hepatic glucose regulating enzyme activities and glycogen level in experimental diabetes. Diabetes mellitus was induced by a single intraperitoneal injection of streptozotocin (STZ) (50 mg/kg b.w.). Five days after STZ injection, diabetic rats received morin (25 and 50 mg/kg b.w.) orally for 30 days. Glibenclamide was used as reference drug. Morin treatment significantly reduced the blood glucose and improved the serum insulin levels. Further, a dose-dependent reduction in glucose-6-phosphatase and fructose-1,6-bisphosphatase was observed along with the increase in liver hexokinase and glucose-6-phosphate dehydrogenase activities. Morin supplement were found to be effective in preserving the normal histological appearance of pancreatic islets as well as to preserve insulin-positive β-cells in STZ-rats. Therefore, these findings suggest that morin displays beneficial effects in the treatment of diabetes, mediated through the regulation of carbohydrate metabolic enzyme activities.     

Combined treatment with naringin and vitamin C ameliorates streptozotocin-induced diabetes in male Wistar rats

Diet and nutrition have substantial impact on reducing the incidence of diabetes mellitus, where oxidative stress is an important etiopathological factor. The combined protective role of low dose of naringin (15 mg kg(-1)) and vitamin C (25 mg kg(-1)) and high dose of naringin (30 mg kg(-1)) and vitamin C (50 mg kg(-1)) on streptozotocin (STZ)-induced toxicity was studied in male Wistar rats. To induce type II diabetes mellitus, rats were injected with STZ intraperitoneally at a dose of 45 mg kg(-1) body weight. STZ-induced diabetic rats showed significant increase in blood glucose, water intake, food intake and glycated hemoglobin and significant decrease in plasma insulin, total hemoglobin, body weight and liver glycogen. Diabetic rats also showed significant decrease in the activity of hexokinase and significant increase in the activities of glucose-6-phosphatase and fructose-1,6-bisphosphatase in liver and kidney. The levels of plasma thiobarbituric acid reactive substances, lipid hydroperoxides and vitamin E were elevated while the level of reduced glutathione was decreased in diabetic rats. Glycoprotein components such as hexose, hexosamine, fucose and sialic acid were increased in plasma, liver and kidney of diabetic rats. Oral administration of high doses of naringin (30 mg kg(-1)) and vitamin C (50 mg kg(-1)) to diabetic rats for a period of 21 days normalized all the above-mentioned biochemical parameters. The effect exerted by naringin (30 mg kg(-1)) and vitamin C (50 mg kg(-1)) was similar to the effect exerted by insulin (6 units kg(-1)). Thus, our study shows the antihyperglycemic and antioxidant effects of naringin and vitamin C in STZ-induced type II diabetes mellitus in rats.     

Antihyperglycemic and antihyperlipidemic activities of methanol:water (4:1) fraction isolated from aqueous extract of Syzygium alternifolium seeds in streptozotocin induced diabetic rats

The present study was taken up to identify potent antihyperglycemic fraction from the aqueous extract of Syzygium alternifolium (SA) seeds, using bioassay guided fractionation. The isolated fraction C at a dose of 50 mg/kg.b.w produced the maximum fall of 83% in the blood glucose level in the diabetic rats after 6 h of the treatment. The administration of fraction C (50 mg/kg.b.w) once daily for 30 days in STZ diabetic rats resulted in a significant decrease in blood glucose, glycosylated haemoglobin with a significant rise in plasma insulin level. Further fraction C showed antihyperlipidemic activity as evidenced by significant decrease in serum TC, TG, LDL-C, VLDL-C levels coupled together with elevation of HDL-C level in diabetic rats. A significant decrease in the activities of SGOT, SGPT, ALP and decreased levels of serum urea and creatinine in diabetic treated rats when compared to diabetic untreated rats, indicate the protective role against liver and kidney damage and non-toxic property of the fraction C. A comparison was made between the action of fraction C and antidiabetic drug glibenclamide (20 mg/kg.b.w). The effect of fraction C was more prominent when compared to that of glibenclamide.     

Hypoglycemic effects of Ganoderma lucidum polysaccharides in type 2 diabetic mice

Our aims were to investigate the hypoglycemic effects and mechanisms of action of Ganoderma lucidum polysaccharides (GLPs) administered for 7 days in type 2 diabetic mice. The mice were randomly divided into four groups (8 mice/group): normal control group, diabetic control group, low-dose GLP-treated diabetic group (50 mg/kg/d), and high-dose GLP-treated diabetic group (100 mg/kg/d). Diabetes was induced by streptozotocin injection and high-fat dietary feeding. At the end of the study, fasting serum glucose, insulin, body weight (BW) and epididymal white adipose tissue weight were measured. The hepatic mRNA levels of glycogen phosphorylase (GP), fructose-1,6-bisphosphatase (FBPase), phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) genes were determined by real-time polymerase chain reaction. Both doses of GLPs significantly decreased fasting serum glucose, insulin and epididymal fat/BW ratio compared with the diabetic control group (p < 0.05). The hepatic mRNA levels of GP, FBPase, PEPCK and G6Pase were significantly lower in both GLP-treated groups compared with the diabetic control group. Taken together, GLPs significantly decrease fasting serum glucose levels in type 2 diabetic mice in a dose-dependent manner. The decreases in fasting serum glucose levels may be associated with decreased mRNA expression levels of several key enzymes involved in gluconeogenesis and/or glycogenolysis.     

Hypoglycemic and β-cells regenerative effects of Aegle marmelos (L.) Corr. bark extract in streptozotocin-induced diabetic rats

The aim of this study was to examine the antidiabetic potential of Aegle marmelos (L.) Corr. (Rutaceae) bark in a diabetic rat model. Dose dependent effects of methanol extract of Aegle marmelos bark (AM) (200 and 400 mg/kg) on blood glucose, plasma insulin, glycated haemoglobin (HbA1c), total protein, hepatic glycogen, marker enzymes of hepatic function and carbohydrate metabolism were evaluated in (streptozotocin) STZ-induced diabetic rats by oral administration for 30 days. Structural integrity of pancreatic islets was assessed by routine histology while, their functional status was assessed by immunolocalization for insulin. High-performance liquid chromatography (HPLC) study established that AM contained antihyperglycemic constituents, aegelin (1.27% w/w) and lupeol (0.29% w/w). AM at 200 and 400 mg/kg showed significant reduction in blood glucose level by 19.14% and 47.32%, respectively in diabetic rats. AM treatment significantly increased insulin level, and produced similar effects on other biochemical parameters. Histological studies showed the regenerative effect of AM on the β-cells of diabetic rats. Immunohistochemical observations in the extract treated diabetic rats showed increased insulin-immunoreactive β-cells. These findings suggest that A. marmelos bark extract has the therapeutic potential in STZ-induced hyperglycemia; hence it can be used in the treatment of diabetes mellitus.     

Intervention of hepatic glucose production. Small molecule regulators of potential targets for Type 2 diabetes therapy

Excessive hepatic glucose production is thought to be a major contributor to the type 2 diabetic state. Drug discovery efforts have yielded small synthetic inhibitors for gluconeogenic and glycogenic regulators of this pathway. The most advanced targets are outlined in this mini-review and include: the glucocorticoid receptor, 11 beta-hydroxysteroid dehydrogenase type 1, fructose 1,6-bisphosphatase, the glucagon receptor, glycogen phosphorylase, glycogen synthase kinase-3, and glucose-6-phosphatase.     

A novel compound from Casearia esculenta (Roxb.) root and its effect on carbohydrate metabolism in streptozotocin-diabetic rats

Casearia esculenta root (Roxb.) is widely used in traditional system of medicine to treat diabetes in India. An active compound 3-hydroxymethyl xylitol (3-HMX) has been isolated and its optimum dose has been determined in a short duration study and patented. In the present study, the long-term effect of 3-HMX in type 2 diabetic rats has been investigated. An optimum dose of 3-HMX (40 mg/kg body weight) was orally administered for 45 days to streptozotocin-diabetic rats for the assessment of glucose, insulin, hemoglobin (Hb), glycated hemoglobin (HbA(1c)), hepatic glycogen, and activities of carbohydrate metabolizing enzymes, such as glucokinase, glucose 6-phosphatase, fructose 1,6-bisphosphatase and glucose-6-phosphate dehydrogenase and hepatic marker enzymes, such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and gammaglutamyl transferase (GGT) in normal and streptozotocin-diabetic rats. 3-HMX at 40 mg dose produced similar effects on all biochemical parameters studied as that of glibenclamide, a standard drug. Histological study of pancreas also confirmed the biochemical findings. These results indicate that 3-hydroxymethyl xylitol, the compound from C. esculenta, possesses antihyperglycemic effect on long-term treatment also.     

Chronic hepatic and renal toxicity by cadmium in rats

Recently there has been an increased interest in the toxic effects from long term exposure of low levels of cadmium (Cd) in diet. Male, Sprague-Dawley rats were treated with 0, 25, 50, 75 ppm Cd mixed in diet continuously for 180 days. A significant decrease in body weight gain was observed in all Cd treated animals. Serum glucose, serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate pyruvic transaminase (SGPT) were increased parallel to Cd concentration and treatment time. Measured hepatic and renal gluconeogenic enzymes, viz. glucose-6-phosphatase, fructose-1, 6-bisphosphatase and phosphoenolpyruvate carboxykinase were increased with higher Cd dose and time. Low concentration of Cd (25 ppm) had minimal effect with shorter treatment length. Fructose-1, 6-bisphosphatase was found to be very sensitive for assessing Cd-induced nephrotoxicity. Increased serum glucose level and gluconeogenic enzyme activities suggest that Cd might interfere in protein metabolism.     

Effect of trichloroethylene (TCE) toxicity on the enzymes of carbohydrate metabolism,brush border membrane and oxidative stress in kidney and other rat tissues

Trichloroethylene (TCE), an industrial solvent, is a major environmental contaminant. Histopathological examinations revealed that TCE caused liver and kidney toxicity and carcinogenicity. However, biochemical mechanism and tissue response to toxic insult are not completely elucidated. We hypothesized that TCE induces oxidative stress to various rat tissues and alters their metabolic functions. Male Wistar rats were given TCE (1000 mg/kg/day) in corn oil orally for 25 d. Blood and tissues were collected and analyzed for various biochemical and enzymatic parameters. TCE administration increased blood urea nitrogen, serum creatinine, cholesterol and alkaline phosphatase but decreased serum glucose, inorganic phosphate and phospholipids indicating kidney and liver toxicity. Activity of hexokinase, lactate dehydrogenase increased in the intestine and liver whereas decreased in renal tissues. Malate dehydrogenase and glucose-6-phosphatase and fructose-1, 6-bisphosphatase decreased in all tissues whereas increased in medulla. Glucose-6-phosphate dehydrogenase increased but NADP-malic enzyme decreased in all tissues except in medulla. The activity of BBM enzymes decreased but renal Na/Pi transport increased. Superoxide dismutase and catalase activities variably declined whereas lipid peroxidation significantly enhanced in all tissues. The present results indicate that TCE caused severe damage to kidney, intestine, liver and brain; altered carbohydrate metabolism and suppressed antioxidant defense system.