Hepatic Glucose 6-phosphate Dehydrogenase Activity Research Articles

High Lipid Content of Prey Fish and n-3 PUFA Peroxidation Impair the Thiamine Status of Feeding-Migrating Atlantic Salmon (Salmo salar) and Is Reflected in Hepatic Biochemical Indices.

Signs of impaired thiamine (vitamin B1) status in feeding-migrating Atlantic salmon (Salmo salar) were studied in three Baltic Sea areas, which differ in the proportion and nutritional composition of prey fish sprat (Sprattus sprattus) and herring (Clupea harengus). The concentration of n−3 polyunsaturated fatty acids (n−3 PUFAs) increased in salmon with dietary lipids and n−3 PUFAs, and the hepatic peroxidation product malondialdehyde (MDA) concentration increased exponentially with increasing n−3 PUFA and docosahexaenoic acid (DHA, 22:6n−3) concentration, whereas hepatic total thiamine concentration, a sensitive indicator of thiamine status, decreased with the increase in both body lipid and n−3 PUFA or DHA concentration. The hepatic glucose 6-phosphate dehydrogenase activity was suppressed by high dietary lipids. In salmon muscle and in prey fish, the proportion of thiamine pyrophosphate increased, and that of free thiamine decreased, with increasing body lipid content or PUFAs, or merely DHA. The thiamine status of salmon was impaired mainly due to the peroxidation of n−3 PUFAs, whereas lipids as a source of metabolic energy had less effect. Organochlorines or general oxidative stress did not affect the thiamine status. The amount of lipids, and, specifically, their long-chain n−3 PUFAs, are thus responsible for generating thiamine deficiency, and not a prey fish species per se.

Rhubarb granule promotes diethylnitrosamine-induced liver tumorigenesis by activating the oxidative branch of pentose phosphate pathway via G6PD in rats

Ethnopharmacological relevanceRhubarb is a natural herbal medicine widely used clinically with numerous pharmacological activities including anti-cancer. Specifically, several studies reported that free anthraquinones from Rhubarb suppressed the proliferation of hepatoma cells. Nonetheless, recent studies revealed that Rhubarb caused hepatotoxicity in vivo, confirming its “two-way” effect on the liver. Therefore, the efficacy and safety of Rhubarb in the in vivo treatment of liver cancer should be further elucidated.Aim of the study: This study investigated the presence of hepatoprotection or hepatotoxicity of Rhubarb in diethylnitrosamine (DEN)-induced hepatocarcinogenesis. Material and methodsA total of 112 male Sprague-Dawley rats weighing 190–250 g were enrolled. The rats were induced hepatocarcinogenesis using diethylnitrosamine (0.002 g/rat) until 17 weeks. Starting at week 11, Rhubarb granules (4 g/kg and 8 g/kg) were intragastrically administered daily for 7 weeks. All rats were euthanized at week 20 and the livers were analyzed via non-targeted metabolomics analysis. We established hepatic glucose 6 phosphate (6PG) levels and glucose 6 phosphate dehydrogenase (G6PD) activities to assess the pentose phosphate pathway (PPP). And the liver injuries of rats were analyzed via histological changes, hepatic function, as well as hepatic protein levels of alpha-fetoprotein (AFP), pyruvate kinase isozyme type M2 (PKM2), and proliferating cell nuclear antigen (PCNA). Furthermore, polydatin (0.1 g/kg/d) as a specific inhibitor of G6PD was used to treat rats. Notably, their histological changes, hepatic function, hepatic 6PG levels, hepatic G6PD activities, PCNA levels, and PKM2 levels were recorded. ResultsNon-targeted metabolomics revealed that Rhubarb regulated the PPP in the liver of Rhubarb-DEN-treated rats. Besides, Rhubarb activated the oxidative branch of the PPP by activating G6PD (a rate-limiting enzyme in the oxidative PPP) in the liver of Rhubarb-DEN-treated rats. Meanwhile, Rhubarb promoted DEN-induced hepatocarcinogenesis. Moreover, polydatin attenuated the promoting effect of Rhubarb on DEN-induced hepatocarcinogenesis. ConclusionsRhubarb promoted DEN-induced hepatocarcinogenesis by activating the PPP, indicating that the efficacy and safety of Rhubarb in the treatment of liver cancer deserve to be deliberated.

Ameliorative properties of Iranian Trigonella foenum-graecum L. seeds and Punica granatum L. peel extracts in streptozotocin-induced experimental diabetic guinea pigs

ObjectiveTo assess the ameliorative properties of Iranian Trigonella foenum-graecum L. (T. foenum-graecum) seeds and Punica granatum L. (P. granatum) peel extracts against streptozotocin-induced diabetes in male guinea pigs. MethodsSixty guinea pigs were divided into six groups (10 guinea pigs per group). Group 1 consisted of normal animals. Groups 2 and 3 were treated with Iranian T. foenum-graecum seeds and P. granatum peel extract alone, respectively. Group 4 was treated with streptozotocin only; whereas Groups 5 and 6 receiving streptozotocin were treated with Iranian T. foenum-graecum seeds and P. granatum peel extract, respectively. All animals were treated for 30 days, and the body weight, blood and liver biochemical parameters were measured. ResultsGuinea pigs exposed to streptozotocin showed an alteration in body weight gain, fasting glucose level, kidney function parameters (blood urea nitrogen and creatinine) as well as decreased serum and hepatic total protein level. In addition, it increased the cholesterol and triglyceride level, while decreasing the hepatic glucose-6 phosphate dehydrogenase activity, glycogen, glutathione content and hepatic catalase activity. Oral treatment with T. foenum-graecum seeds and P. granatum peel extracts revealed significant protective properties with respect to body weight gain and other biochemical parameters studied. ConclusionsThe Iranian T. foenum-graecum seeds and P. granatum peel extracts are significantly potent in ameliorating diabetic condition induced by streptozotocin and improving various biochemical parameters in serum and liver of guinea pigs.

Ameliorative effect of Withania coagulans on hyperglycaemia and oxidative stress

Introduction: Management of diabetes mellitus always begins with improving glycaemic control by modification of diet, use of oral hypoglycaemic agents and insulin supplementation. However, owing to a steady increase in the dosage of treatment with time and adverse side-effects, there is a demand for new compounds to manage diabetes mellitus. Withania coagulans is a natural product with folkloric medicinal use for chronic disorders of liver, dyspepsia, flatulent coli, intestinal infections, ulcers, rheumatism, bronchitis and degenerative diseases. However, there is lack of information regarding its effect on chronic diabetes mellitus. Objectives: We aimed to evaluate the antihyperglycaemic effect of aqueous W. coagulans extract on hepatic glucose-6-phosphate dehydrogenase (G6PDH) activity and oxidative stress in acute and chronic diabetic models. Materials and methods: The screening of the most effective dose of W. coagulans was determined by postprandial glucose test in streptozotocin (STZ) diabetic rats. The beneficial effects of administration of W. coagulans (10mg/kg) for 21 days on body weight, blood glucose, hepatic G6PDH activity, reduced glutathione (GSH) and malondialdehyde (MDA) were investigated in acute and chronic STZ diabetic rats. Results: W. coagulans (10mg/kg) significantly inhibited the postprandial rise in blood glucose level after food administration at 60, 120 and 240 minutes in STZ rats, compared with control. Twenty-one-day treatment with W. coagulans resulted in significant improvements in body weight and glycaemic control in both acute and chronic diabetic groups. The levels and activities of hepatic G6DPH activity, GSH and MDA were either significantly increased or near normal due to treatment. Conclusions: W. coagulans demonstrated antihyperglycaemic activity in diabetic rats. The beneficial effect was associated with increased hepatic glucose uptake and decrease in oxidative stress, which may attenuate diabetic complications. These data suggest that the dietary intake of W. coagulans may reinforce the effect of existing treatments for diabetes mellitus.

Glutathion Peroxidase and Glucose-6-Phosphate Dehydrogenase Activities in Bovine Blood and Liver

A total of 46 cattle, including 25 as control, 16 with glycogen degeneration and 5 with severe fatty degeneration were studied. Whole blood and liver tissue specimens were used to measure glutathione peroxidase (GSH-Px) and Glucose-6-Phosphate Dehydrogenase (G6PD) activities. The present study determined the value of these parameters in diagnosing glycogen and fatty degeneration in cattle from the point of the status of antioxidation and lipid peroxidation. The results showed a significant decrease in hepatic GSH-Px activity and a significant increase in hepatic G6PD activity in cases of fatty degeneration. On the other hand, there were no significant changes in erythrocytic and hepatic GSH-Px and G6PD activities in cases of glycogen degeneration. The results indicated lipoperoxidation process in the liver tissues increased in cases of fatty degeneration. Therefore, supplying animals suffering from fatty liver with sufficient quantities of nutrient antioxidants may be valuable when treatment is considered.

Species-specific alteration of hepatic glucose 6-phosphate dehydrogenase activity with coplanar polychlorinated biphenyl: Evidence for an Ah-receptor - linked mechanism

We examined the in vivo effect of a highly toxic coplanar polychlorinated biphenyl (PCB) on the hepatic activity of glucose 6-phosphate dehydrogenase (G6PDH) in aryl hydrocarbon (Ah)-responsive (C57/BL) and -less-responsive (DBA) strains of mice. The activity in the C57BL strain was moderately increased by 3,3′,4,4′,5-pentachlorobiphenyl (PCB 126) in a dose dependent manner. However, this was not observed in DBA mice although greater doses were injected. 2,2′,5,5′-Tetrachlorobiphenyl (PCB 52) with a non-planar structure did not increase G6PDH activity. The increase in G6PDH activity with PCB 126 was also seen in rats, but not in guinea pigs. The activity in the latter species was decreased rather than increased. These results suggest that the induction of hepatic G6PDH by coplanar PCB is mediated by a mechanism involving the Ah receptor, and the response was highly species-specific.

Determinants of hydroperoxide detoxification in diabetic rat intestine: Effect of insulin and fasting on the glutathione redox cycle

The capacity for hydroperoxide detoxification in diabetic (DM) intestine was studied in streptozocin-induced DM rats by quantification of the intestinal glutathione (GSH) redox cycle, a key cellular pathway for peroxide elimination. A role for luminal glucose in regulation of redox cycle activity was examined in insulin-treated or 24-hour—fasted DM animals. Intestinal activities of the redox enzymes, GSH peroxidase, GSSG reductase, and glucose-6-phosphate dehydrogenase (G6PD), were significantly decreased by 17 hours' insulin treatment, whereas only G6PD was decreased by fasting. Mucosal GSH levels were also markedly decreased under these conditions. These results are consistent with an overall suppression of intestinal GSH redox cycle function by short-term administration of insulin. Insulin treatment for 7 consecutive days increased hepatic G6PD activity by fourfold but was without effect on intestinal G6PD, suggesting tissue specificity in insulin regulation of G6PD. The rate of metabolism of tert-butyl hydroperoxide ( tBH) in isolated enterocytes was low in the absence of substrates (0.51 ± 0.07 nmol/10 6 cells/min) but was increased fivefold by exogenous glucose (2.70 ± 0.11 nmol/10 6 cells/min), indicating that glucose availability is an important contributor to intestinal detoxification of toxic hydroperoxides. Collectively, the current results show that GSH redox cycle enzymes in DM intestine are under coordinate insulin control, and that this control appears to be downregulated by short-term insulin treatment.

Hypoglycaemic activity of Coccinia indica and Momordica charantia in diabetic rats: depression of the hepatic gluconeogenic enzymes glucose-6-phosphatase and fructose-1,6-bisphosphatase and elevation of both liver and red-cell shunt enzyme glucose-6-phosphate dehydrogenase

Coccinia indica leaves were extracted with 60% ethanol, solvents were evaporated and the residue was suspended in water. This suspension was administered orally at a dose of 200 mg/kg body wt. after 18 h of fasting to normal fed and streptozotocin-induced male diabetic rats (180-250 g). After 90 min the rats were killed, and blood-glucose, hepatic glucose-6-phosphatase, fructose-1,6-bisphosphatase and glucose-6-phosphate dehydrogenase (G6PDH) and red-cell G6PDH were assayed. Blood sugar was depressed by 23% (P < 0.01) and 27% (P < 0.001) in the normal fed and streptozotocin-diabetic rats respectively compared with controls which were given distilled water. Hepatic glucose-6-phosphatase and fructose-1,6-bisphosphatase activities were depressed by 32% (P < 0.001) 30% (P < 0.05) respectively in the streptozotocin-diabetic rats, compared with 19% (P < 0.02) and 20% (P < 0.01) depression in the normal fed controls, whereas both the red-cell and hepatic G6PDH activities were found to be elevated by feeding the extract in the streptozotocin-diabetic and in the normal fed controls. Similar results were obtained with the 95%-ethanolic extract of Momordica charantia. Taken together, these results indicate that Coccinia indica and Momordica charantia extracts lowered blood glucose by depressing its synthesis, on the one hand through depression of the key gluconeogenic enzymes glucose-6-phosphatase and fructose-1,6-bisphosphatase and on the other by enhancing glucose oxidation by the shunt pathway through activation of its principal enzyme G6PDH.

The multiple forms of liver glucose-6-phosphate dehydrogenase in spontaneously and prematurely weaned rats

The various molecular species of rat liver glucose-6-phosphate dehydrogenase (G6PD) were assayed during and immediately after weaning. Three dimeric forms were detected, but tetramers and hexamers were absent. Spontaneous weaning to the maternal diet was associated with an increase in the percentage of G6PD activity contributed by G6PD-III, at the expense of G6PD-I and G6PD-II. These changes occurred sooner when the rats were prematurely weaned on postnatal day 17. The percentage distribution of G6PD activity among the dimeric forms was not correlated with liver glutathione (GSH) content, or with the ratio of G6PD activity to GHS levels, suggesting that liver GSH content as such may not be the primary factor responsible for regulating the proportions of G6PD activity present in each form. It appears that interconversions involving the tetrameric and hexameric forms of G6PD, probably do not contribute to the control of hepatic G6PD activity during the weaning period. The data also suggest that the rise in hepatic G6PD activity attendant on weaning may be associated with decreased enzyme degradation.

Regulation of liver and brain hexose monophosphate dehydrogenases by insulin and dietary intake in the female rat.

Liver glucose 6-phosphate dehydrogenase and phosphogluconate dehydrogenase activities were significantly decreased in both diabetic and fasted rats. Treatment of diabetic rats with insulin resulted in liver glucose 6-phosphate dehydrogenase and phosphogluconate dehydrogenase activities that were significantly greater than controls. Insulin promoted an increase in food consumption that was blocked by adrenaline. Insulin, when administered together with adrenaline, restored hepatic glucose 6-phosphate dehydrogenase and phosphogluconate dehydrogenase activities of diabetic animals to control values, without altering food consumption. Brain glucose 6-phosphate dehydrogenase and phosphogluconate dehydrogenase activities were not significantly altered by either dietary restriction, diabetes or insulin treatment. These results demonstrate a dissociation between the action of insulin on hepatic glucose 6-phosphate dehydrogenase activity and its action to increase food intake.

A critical appraisal of the effect of oxidized glutathione on hepatic glucose 6-phosphate dehydrogenase activity.

Experiments were undertaken to elucidate the mechanism of the reversal of NADPH inhibition of rat liver glucose 6-phosphate dehydrogenase by oxidized gluthathione alone and in combination with a putative cofactor described by Eggleston & Krebs [(1974) Biochem. J. 138, 425-435]. Evidence is presented that this reversal is largely an artifact, caused by the incorrect application of a control assay procedure and a spurious effect of Zn2+ (added in order to inhibit glutathione reductase) in crude enzyme solutions. When the proper assay procedure is used and glutathione reductase is inhibited with low concentrations of Hg2+, glutathione addition has no effect on NADPH inhibition of glucose 6-phosphate dehydrogenase. No evidence was found for the existence of a cofactor that mediates an effect of glutathione on glucose 6-phosphate dehydrogenase.

Biochemical adaptation of rat liver in response to marginal oxygen toxicity.

1. Hepatic glucose 6-phosphate dehydrogenase activity was increased in rats exposed to 5lb/in(2) (equivalent to 27000ft), 100% O(2) when compared with control animals in a 14.7lb/in(2) (sea level), air environment. Glyceraldehyde 3-phosphate dehydrogenase, isocitrate dehydrogenase, and succinate dehydrogenase were not affected by the 5lb/in(2), 100% O(2) environment. 2. Animals exposed to the hyperoxic environment consumed food, expired CO(2) and gained weight at the same rate as normoxic control animals. Additionally, blood glucose and liver glycogen concentrations were unchanged in the hyperoxic animals. The only readily apparent physiological difference in the hyperoxic animals was a decreased haematocrit. 3. The increase in glucose 6-phosphate dehydrogenase was eliminated by the injection of actinomycin D or cycloheximide. 4. Expiration of (14)CO(2) from [1-(14)C]glucose was approximately the same in hyperoxic and normoxic rats. However, (14)CO(2) expiration from [6-(14)C]glucose was markedly decreased in the animals exposed to the hyperoxic environment. 5. Calculations of the relative importance of the pentose phosphate pathway versus the tricarboxylic acid cycle plus glycolysis indicated that the livers from animals in the 5lb/in(2), 100% O(2) environment metabolized twice as much carbohydrate by way of the pentose phosphate pathway as did those from the sea-level air control animals. 6. In livers of rats exposed to 5lb/in(2), 100% O(2) the concentrations of pyruvate, citrate and 2-oxoglutarate were increased, that of isocitrate was slightly elevated, whereas the concentrations of succinate, fumarate and malate were decreased. 7. An inactivation of both tricarboxylic acid cycle lipoate-containing dehydrogenases, pyruvate and 2-oxoglutarate, under hyperoxic conditions is proposed. 8. The adaptive significance of the induction of glucose 6-phosphate dehydrogenase and the resultant production of NADPH under hyperoxic conditions is discussed.

Response of Lipogenesis to Repletion in the Pyridoxine-deficient Rat

Pyridoxine has been implicated in fat metabolism. To elucidate its role the response of lipogenetic activities in the liver and epididymal pad of deficient rats to pyridoxine administration was measured. Rats were fed a pyridoxine-deficient diet until they ceased to gain weight (40 days); they were then repleted by the subcutaneous injection of 300 μg pyridoxine·HCl/rat every day for 5 days. During repletion, diets varying in fat content (0 to 25%) were fed. The administration of the vitamin resulted in increases in the liver and epididymal glucose 6-phosphate dehydrogenase which were small in the pair-fed group and substantial in the ad libitum-fed controls. The enzyme activity was highest (five fold) in rats receiving the fat-free diet. The substitution of starch for sucrose resulted in lower levels of dehydrogenase acitvity. In animals fed ad libitum and repleted with the same basal diet, the liver lipids, the hepatic glucose 6-phosphate dehydrogenase activity and the extent of acetate-14C incorporation into liver lipids were high on day 2 of repletion and returned to normal levels by day 11 with a concomitant increase in carcass fat, approaching the levels in controls maintained with a pyridoxine-sufficient diet through-out the experiment. The data demonstrate that the role of pyridoxine in lipogenesis may be mediated through the increase in food intake with the repletion of the vitamin.