Studies on the effect of sodium arsenate on the enzymes of carbohydrate metabolism,brush border membrane,and oxidative stress in the rat kidney

Arsenic is an environmental pollutant and its contamination in drinking water poses serious world wide environmental health threats. It produces multiple adverse effects in various tissues, including the kidney. However, biochemical mechanism and renal response to its toxic insult are not completely elucidated. We hypothesized that sodium arsenate (ARS) induces oxidative stress and alters the structure and metabolic functions of kidney. Male Wistar rats were administered ARS (10 mg/kg body weight/day), intraperitoneally daily for 10 days. ARS administration increased blood urea nitrogen, serum creatinine, cholesterol, glucose, and phospholipids but decreased inorganic phosphate, indicating kidney toxicity. The activity of brush border membrane (BBM) enzymes significantly lowered in both cortex and medulla. Activity of hexokinase, lactate dehydrogenase, glucose-6-phosphate dehydrogenases, and NADP-malic enzyme significantly increased whereas malate dehydrogenase, glucose-6-phosphatase, and fructose 1,6 bis phosphatase decreased by ARS exposure. The activity of superoxide dismutase, GSH-peroxidase, and catalase were selectively altered in renal tissues along with an increase in lipid peroxidation. The present results indicated that ARS induced oxidative stress caused severe renal damage that resulted in altered levels of carbohydrate metabolism and BBM enzymes.     

Sodium chlorate,a major water disinfection byproduct,alters brush border membrane enzymes,carbohydrate metabolism and impairs antioxidant system of Wistar rat intestine

Sodium chlorate (NaClO₃) is a widely used nonselective herbicide. It is also generated as a by‐product during disinfection of drinking water by chlorine dioxide. The purpose of this study was to evaluate the effect of NaClO₃ on rat intestine. Adult male rats were randomly divided into five groups: control and remaining four groups were administered orally different doses of NaClO₃ and sacrificed 24 h after the treatment. The administration of NaClO₃ produced acute oxidative stress in the intestine, which manifested in the form of markedly enhanced malondialdehyde levels and carbonyl content and lowered total sulfhydryl groups and glutathione levels. The activities of several brush border membrane (BBM) enzymes were greatly reduced as compared to control. There were alterations in the activities of various enzymes of carbohydrate metabolism and those involved in maintaining the antioxidant defense system. Histological studies support the biochemical results showing NaClO₃ dose‐dependent increase in tissue damage. Thus, the present study shows that oral administration of NaClO₃ decreases the activities of BBM enzymes, induces oxidative stress, alters metabolic pathways, and impairs the antioxidant system of rat intestine. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1607–1616, 2017.     

Antihyperglycaemic effect of Cassia auriculata in experimental diabetes and its effects on key metabolic enzymes involved in carbohydrate metabolism

1. In experimental diabetes, enzymes of glucose and fatty acid metabolism are markedly altered. Persistent hyperglycaemia is a major contributor to such metabolic alterations, which lead to the pathogenesis of diabetic complications. To our knowledge, there are no available reports on the enzymes of hepatic glucose metabolism of Cassia auriculata flower against diabetes. The present study was designed to study the effect of Cassia auriculata flower extract (CFEt) on hepatic glycolytic and gluconeogenic enzymes. 2. Streptozotocin diabetic rats were given CFEt (0.15, 0.30 and 0.45 g/kg) or 600 microg/kg glibenclamide for 30 days. At the end of 30 days, blood glucose, plasma insulin, haemoglobin, glycosylated haemoglobin, glycolytic and gluconeogenic enzymes were assessed. 3. Administration of CFEt at 0.45 g/kg significantly decreased blood glucose, glycosylated haemoglobin and gluconeogenic enzymes and increased plasma insulin, haemoglobin and hexokinase activity. Similarly, administration of glibenclamide showed a significant effect; however, CFEt at 0.15 and 0.30 g/kg did not show any significant effect. 4. In conclusion, the observations show that the aqueous extract of CFEt possesses an antihyperglycaemic effect and suggest that enhanced gluconeogenesis during diabetes is shifted towards normal and that the extract enhances the utilization of glucose through increased glycolysis. The effect of CFEt was more prominent than that of glibenclamide.     

Lack of effect of streptogramins on hepatic drug metabolism enzymes in the rat.

Male Sprague-Dawley rats were treated with streptogramin derivatives (RP 7293, RP 54476, RP 57669, and RP 59500) or with the macrolide troleandomycin. Liver cytosol and microsomes were prepared, and the in vitro transformation of several model substrates studied. Furthermore, total and complexed microsomal cytochrome P-450 levels were compared. Hepatic cytochrome P-450 metabolite complexes were detected 4 days after troleandomycin treatment (500 mg/kg/day po), whereas such effects were not observed with po RP 7293 (500 mg/kg/day, 4 days) or with iv RP 54476 (12 mg/kg/day, 7 days), RP 57669 (6 mg/kg/day, 7 days), or RP 59500 (6 and 18 mg/kg/day, 7 days). The administration of troleandomycin resulted in statistically significant increases in liver weight (+20%), microsomal protein (+70%), total cytochrome P-450 (+187%), and cytosolic glutathione S-transferase activity (+32%). The activities of aniline hydroxylase, aminopyrine N-demethylase, and the high and low phases of 7-ethoxyresorufin O-deethylase were markedly decreased by 36% to 56%. In contrast, none of these hepatic parameters was changed significantly after administration of each streptogramin. These results suggest that streptogramins have not, in contrast to many commonly used macrolide antibiotics, had potent or specific effects on hepatic drug metabolizing enzymes in rats.     

Effect of ochratoxin A on carbohydrate metabolism in rat liver

The effect of ochratoxin A on the carbohydrate metabolism of liver has been investigated in rats. A marked depletion of glycogen in liver and an increase of serum glucose in ochratoxin A-treated rats were noted. Glycogen synthetase (I and total) activities were reduced. In contrast, phosphorylase a activity was increased in the liver of ochratoxin A-treated rats. Decrease in incorporation of [¹⁴C]-glucose into hepatic glycogen confirmed the findings using unlabeled glucose. These results implied that depletion of hepatic glycogen in ochratoxin A-treated rats was attributed to the inhibition of the active transport of glucose into liver tissue, suppression of glycogenesis, and acceleration of glycogenolysis.     

Influence of hormonal contraceptives on carbohydrate and lipid metabolism in the rat

The effect of low, physiological doses of hormonal contraceptives on carbohydrate and lipid metabolism in the female rat was investigated. Animals were treated, by subcutaneous njection, for 14 days with a combination of 5 μg/kg ethynyl estradiol + 50 μg/kg dl-norgestrel, 5 μg/kg ethynyl estradiol + 400 μg/kg norethindrone acetate and with the single components only. Blood glucose in fasted animals was not altered. There was a dose-dependent increase in glycogen deposition in liver. This effect was confined to the estrogenic component and was dependent on the presence of the adrenal gland. The sensitivity of the organism towards exogenous insulin was not changed. In an insulin sensitive system, e.g. in isolated fat cells, the conversion of glucose-1-¹⁴C to ¹⁴CO₂ was not significantly altered, neither in the presence nor in the absence of insulin. Treatment of rats with ethynyl estradiol was associated with a highly significant increase in serum triglycerides, a transient reduction in serum total cholesterol and a decrease in total lipids in liver. Similar effects were observed after administration of the combination of ethynyl estradiol + dl-norgestrel. The estrogen-induced increase in serum triglycerides was, however, abolished by simultaneous treatment with norethindrone acetate. Liver lipids remained reduced. Neither gestagen substantially altered lipid metabolism. Free fatty acids in serum of fasted and fed rats were unaltered after ethynyl estradiol. There was no increased lipolytic rate with epinephrine, as measured in isolated fat cells. The antilipolytic effect of insulin was not significantly changed in animals treated with ethynyl estradiol and ethynyl estradiol + dl-norgestrel. The experiments demonstrate that the estrogenic component of hormonal contraceptives is mainly responsible for the metabolic changes seen in the rat. It is suggested that the gestagens may play an important role in modifying the effects of estrogens on carbohydrate and lipid metabolism.     

Pre- and postnatal carbohydrate metabolism of rat lung tissue

The effect of maternal nicotine exposure on fetal and neonatal lung metabolism was investigated. Nicotine (0.25 and l.0 mg/kg body weight/day) administered subcutaneously to the mother animal from day 7 of gestation until weaning led to retarded glycogenolysis of fetal lung. This was due to an inhibition of lung glycogen phosphorlyase. Exposure until 2 weeks after birth had no effect on the in vitro oxygen consumption of lung tissue, but the total glucose turnover of rat neonates exposed to 0.25 and 1.0 mg nicotine/kg body weight per day was increased to 78.96±3.92 and 121.09±7.36 mol/g per h, respectively, as compared to controls (64.95±4.56 mol/g per h). In contrast to the marked increase in total glucose turnover, the in vitro lactate production was significantly lowered, suggesting an inhibition of the glycolytic pathway. The lung lecithin content of control neonates (day 1 post-partum) was 1.94±0.30 mg/g wet tissue mass. Nicotine administration to the mother resulted in a 92% higher lung lecithin content (3.72±0.06 mg/g). The results suggest that although nicotine will have no effect on the incidence of respiratory distress syndrome due to a lack of lecithin, it may have a detrimental effect on the functional development of the lung as a result of its inhibitory effect on glucose oxidation via the glycolytic pathway.     

The effect of trans-stilbene oxide and other structurally related inducers of drug-metabolizing enzymes on the pentose phosphate pathway and other enzymes of carbohydrate metabolism

trans-Stilbene oxide has been found earlier to be a new type of inducer of drug-metabolizing systems. Here we demonstrate that treatment of rats with this xenobiotic results in an increase in the activity of the cytosolic glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase, the first and third enzymes in the pentose phosphate pathway, to 350% and 170% of the control values, respectively. At the same time microsomal glucose 6-phosphate dehydrogenase activity was unaffected by administration of trans-stilbene oxide or benzil. The time course and dose-response of the increases in glucose 6-phosphate and 6-phosphogluconate dehydrogenase activities have been characterized. The activities of ribulose 5-phosphate 3-epimerase and ribose 5-phosphate ketol isomerase, enzymes further along in the pentose phosphate pathway, were not significantly affected by trans-stilbene oxide or benzil. An investigation of the effect of treating rats with different metabolites of stilbene and with other structurally related compounds on hepatic cytosolic glucose 6-phosphate dehydrogenase activity revealed the structural features which are important for increasing this activity. Finally, it was found that administration of trans-stilbene oxide did not affect the activities of glucokinase and phosphoglucose isomerase, the two glycolytic enzymes which can produce glucose 6-phosphate, the link between glycolysis and the pentose phosphate shunt.     

Effect of amiodarone on the membrane bound enzymes of rat intestine

Amiodarone, a cationic amphiphile known for its clinical efficacy as an antiarrhythmic agent, unfortunately causes serious side effects. The present study was undertaken to investigate its intestinal toxicity, on oral administration, using a Wistar rat model. The relationship of drug dose and duration on intestinal toxicity was investigated. Optimum changes were observed after 21 days of AD administration at a dose of 175 mg/Kg body wt/day and this dosage was used for further studies. Histological studies revealed decreased villi and crypt size and reduction in the cellularity of lamina propria. Marked reduction in the activities of Ca(2+)-ATPase, alkaline phosphatase, disaccharidases and Na+, K(+)-ATPase was observed. The reduction in the uptake of 14C-glucose and 14C-glycine, in vivo, was correlated to the reduction in the activities of these enzymes. The reduction in the activities of the intestinal membrane bound enzymes may be attributed to altered morphology of the villi and crypts.     

The effect of 5-methylpyrazole-3-carboxylate and nicotinic acid on abnormalities of carbohydrate metabolism in alloxan-diabetic rat muscle

The administration of the antilipolytic agents sodium nicotinate (1 mmole/kg i.p.) or sodium 5-methylpyrazole-3-carboxylate (0.5 or 1.0 mmole/kg i.p.) to alloxan-diabetic rats produced a significant reduction in the plasma concentration of free fatty acids and a slight reduction in blood glucose concentration. The concentrations in the freeze-clamped heart of citrate, acetyl CoA, glucose-6-phosphate and fructose-6-phosphate were increased in untreated alloxan-diabetic rats relative to normoglycaemic controls. Treatment of alloxan-diabetic rats with the antilipolytic agents or insulin (60 U/kg i.p.) lowered these increased concentrations of metabolites in the heart. Treatment of the diabetic rats with the antilipolytic agents also produced an increase in the activity of pyruvate dehydrogenase in heart, but only treatment with 5-methylpyrazole-3-carboxylate had a significant effect on the activity of the enzyme in freeze-clamped soleus muscle.     

The action of hypoglycaemic sulphonylureas on carbohydrate metabolism in the fasted rat

Tolbutamide and carbutamide given orally to fasted rats cause a rise in the liver glycogen content 1½ to 3½ hr. after administration of the drugs. Glycogen accumulates preferentially in the right lobe. Subcutaneously injected tolbutamide has the same effect. Both sulphonylureas cause inhibition of glucose-6-phosphatase activity of rat liver homogenates in vitro, but at drug concentrations comparable with those found in plasma of treated patients the degree of inhibition is less than 10%. Livers from treated rats show normal glucose-6-phosphatase activity. The glucose uptake of the isolated rat diaphragm is unaffected by the sulphonylureas added in vitro. Diaphragms from treated rats show normal glucose uptake in the presence or absence of insulin. The inferences to be drawn from these results are discussed in the light of previous work. It is concluded that the sulphonylureas exert hypoglycaemic action by inhibiting glycogenolysis and it is suggested that they might do so by inhibiting release of glucagon from the pancreas.