Effect of the sulfonylurea glyburide on glycogen synthesis in alloxan-induced diabetic rat hepatocytes

• 1.1. The effect of glyburide (glibenclamide) treatment on the liver glycogen levels of diabetic rats have been studied.
• 2.2. 3 weeks treatment with glyburide (5 mg/kg, orally) increased liver glycogen and decreased blood glucose levels.
• 3.3. The results of this study demonstrated that the sulfonylurea, glyburide is capable of exerting direct insulin-like effects on liver glycogen values in vivo.

     

The effects of the sulfonylurea glyburide on glutathione peroxidase, superoxide dismutase and catalase activities in the heart tissue of streptozotocin-induced diabetic rat

Oxygen free radicals have been suggested to be a contributory factor in diabetes complications. The aim of this study was to examine the effects of glyburide on the antioxidant enzyme activities in the heart tissue of diabetic rats. We investigated the activities of antioxidant enzymes (superoxide dismutase, catalase and glutathione peroxidase) in the hearts of both control and streptozotocin-induced diabetic rats. In the heart of diabetic rats, the activity of total superoxide dismutase decreased significantly (p < 0.005), whereas the activity of catalase and glutathione peroxidase increased to a large extent (p < 0.0001 and p = 0.05, respectively) at the end of the fourth week compared with the control group. Glyburide treatment of diabetic rats for 4 weeks corrected the changes observed in diabetic heart. In addition, blood glucose levels of untreated diabetic rats decreased following the glyburide treatment. These results demonstrate that the sulfonylurea glyburide is capable of exerting direct insulin-like effect on heart superoxide dismutase, catalase and glutathione peroxidase activities of diabetic rats in vivo.     

Effect of the sulfonylurea glyburide on superoxide dismutase in streptozotocin-induced diabetic rat muscle

• 1.1. The effect of glyburide (glibenclamide) treatment on the muscle superoxide dismutase (SOD) activity of diabetic rats has been studied.
• 2.2. Four weeks of treatment with glyburide (5 mg/kg, orally) increased muscle SOD activity and decreased blood glucose levels.
• 3.3. The results of this study demonstrate that the sulfonylurea, glyburide, is capable of exerting direct insulinlike effects on muscle SOD activity in vivo.

     

Effect of garlic on the hepatic glutathione S-transferase and glutathione peroxidase activity in rat

It was attempted to observe the effect of garlic on the hepatic glutathione s-transferase and glutathione peroxidase activity in this study. Glutathione s-transferase (EC 2.5.1.18) are thought to play a physiological role in initiating the detoxication of potential alkylating agents, inclnding pharmacologically active compounds. Glutathione peroxidase (EC 1.11.1.9) might play an important role in the protection of cellular structures against oxidative challenge. The activities of glutathione s-transferase and glutathione peroxidase in rat liver were increased by the treatment of garlic juice. Allicin fraction, heat-treated allicin fraction and garlic butanol fraction markedly inhibited glutathione s-transferase activityin vitro, whereas glutathione peroxidase activity was significantly increased in heat-treated allicin fraction and garlic butanol fraction.     

Effect of butylated hydroxytoluene on glutathione S-transferase and glutathione peroxidase activities in rat liver

When rats were fed a diet containing 0.4% (w/w) butylated hydroxytoluene (BHT), glutathione (GSH) S-transferase activity towards 1-chloro-2,4-dinitrobenzene (CDNB) increased approximately 3-fold in the liver. Immunotitration studies using the antibodies raised against rat liver GSH S-transferase B and GSH S-transferase A and C indicated that the increase in GSH S-transferase activity was probably due to de novo protein synthesis. Since some forms of rat liver GSH S-transferases express GSH peroxidase II activity, a concomitant increase in GSH peroxidase II was expected. However, GSH peroxidase II activity in the liver of BHT-treated rats remained unchanged. Gel filtration of supernatant fractions from livers of control and BHT-treated rats, followed by isoelectric focusing, indicated that BHT induced the activity of hepatic GSH S-transferases, without any apparent effect on GSH peroxidase II activity.     

Non-selenium-dependent glutathione peroxidase activity in rat lung: Association with lung glutathione S-transferase activity and the effects of hyperoxia

To determine if non-selenium-dependent glutathione peroxidase (Non-Se GSH-Px) activity is present in rat lung, we fractionated rat lung soluble fractions from rats fed a selenium-deficient or control diet and measured glutathione peroxidase activity with both cumene hydroperoxide and hydrogen peroxide as substrates. We also measured glutathione S-transferase (GSH S-transferase) activity in the fractions with 1-chloro-2,4-dinitrobenzene as substrate. Non-Se GSH-Px activity was present (about 34% of total GSH-Px activity), and the peak present in the gel filtration chromatogram coeluted with the GSH S-transferase peak. We then measured GSH S-transferase activity in lung-soluble fractions from rats exposed to room air or 85% O₂ for 5 days. Lung GSH S-transferase activity was increased in the oxygen-exposed animals when compared to the air-exposed controls. The increase in GSH S-transferase activity could represent the induction of lung non-Se GSH-Px activity.     

Acinar distribution of glutathione-dependent detoxifying enzymes. Low glutathione peroxidase activity in perivenous hepatocytes

The acinar distribution of glutathione S-transferase (GST), glutathione peroxidase (GPx), glutathione reductase (GR), and glucose-6-phosphate dehydrogenase (G-6-PDH) was examined by analyzing periportal (p.p.) and perivenous (p.v.) rat hepatocytes selectively isolated by the digitonin-collagenase perfusion. The cytosolic GST activity was higher in p.v. cells, but the microsomal GST and cytosolic GR were found to be evenly distributed in the acinus. In contrast, the activity of both the Se-dependent GPx and the microsomal (Se-independent) GPx, as well as G-6-PDH, was much lower in the p.v. than in the p.p. cells. The heterogeneous distribution of GST, GPx and G-6-PDH was confirmed by analyzing liver perfusion effluents collected after ante- or retrograde digitonin infusion. The relatively low activities of GPx and G-6-PDH in the p.v. cells could partly explain the susceptibility of this region to chemical injury.     

合用N-乙酰半胱氨酸和牛磺酸对实验性糖尿病大鼠的作用

目的观察合用N-乙酰半胱氨酸和牛磺酸对四氧嘧啶诱发糖尿病大鼠的作用。方法实验组灌胃给予N-乙酰半胱氨酸和牛磺酸各125mg/(d·kg),连续28d,然后测定空腹血糖浓度、血浆超氧物歧化酶(SOD)活性和全血脂质过氧化物(LPO)含量。结果合用N-乙酰半胱氨酸和牛磺酸具有明显的降血糖作用(P<0.01),并可使糖尿病大鼠全血IPO含量显著下降(P<0.01)、血浆SOD的活性明显增加(P<0.05)。结论N-乙酰半胱氨酸和牛磺酸可显著改善四氧嘧啶诱发糖尿病大鼠的糖代谢,二者合用可显示出较强的抗氧化作用。     

Differential regulation of hepatic glutathione transferase and glutathione peroxidase activities in the rat

The effects of the xenobiotics, i.e. butylated hydroxytoluene, beta-naphthoflavone, isosafrole, pregnenolone-16 alpha-carbonitrile, trans-stilbene oxide, 3-methylcholanthrene, phenobarbital, 3,3',4,4'-tetrachlorobiphenyl, 2,2',4,4',5,5'-hexachlorobiphenyl, on rat liver cytosolic glutathione transferase and glutathione peroxidase activities have been investigated. Although the glutathione transferase isozymes (measured by the specific substrates ethacrynic acid and delta 5-androstene-3,17-dione) which have been shown to possess peroxidase activity were significantly increased, little or no increase in peroxidase activity (toward cumene hydroperoxide, tert-butyl hydroperoxide or hydrogen peroxide) was observed. Likewise during a 16-day time course following the administration of Aroclor 1254 or fireMaster BP-6 (each 500 mg/kg, i.p.), potent induction of glutathione transferase activities was seen without any significant increases in peroxidase activities. In fact during the second week of the time course, there were significant decreases in selenium-dependent glutathione peroxidase activity (toward hydrogen peroxide). The inverse regulation of these activities, i.e. the depression of selenium-dependent glutathione peroxidase activity following sustained induction of glutathione transferases, may have direct implications for the toxicity of the polyhalogenated aromatic hydrocarbons.     

Glutathione peroxidase and glutathione transferase activity in rat lung and liver following cadmium inhalation

A 2-h inhalation exposure to 4.6 mg Cd/m3 decreased pulmonary total glutathione peroxidase (GSH Px) activity and non-selenium peroxidase (GSH non-Se-Px) activity but had no effect on GSH selenium peroxidase (Se-Px) activity. Seventy-two hours after exposure there was an increase in total GSH Px and GSH Se-Px activity and a decrease in GSH non-Se-Px activity. Exposure to 0.44 mg Cd/m3 for 2 h caused no effect on GSH Se-Px at either 0 or 72 h post exposure, but total GSH Px and GSH non-Se-Px activities were decreased up to 72 h post exposure. Exposure to 4.6 mg Cd/m3 caused an increase in hepatic GSH Se-Px activity 72 h post exposure, but no other significant changes were observed in the liver. Changes in GSH non-Se-Px activity did not relate to changes in GSH transferase (Tr) activity. The data suggest that alterations in GSH Px activity by Cd2+ may be due to changes in GSH non-Se-Px activity and that changes in pulmonary GSH Tr and GSH non-Se-Px activities may not be as closely linked as in the liver.     

Endrin-induced depletion of glutathione and inhibition of glutathione peroxidase activity in rats

1. Recent studies have shown that endrin induces lipid peroxidation and may produce toxicity through an oxidative stress. We have therefore examined the effect of endrin administration to rats on glutathione content and the activities of glutathione metabolizing enzymes. 2. The oral administration of endrin resulted in dose- and time-dependent decreases in hepatic and renal glutathione content with maximum depletion (90%) occurring in liver at approximately 24 hr post-treatment. 3. Decreases in glutathione content were also observed in lung, brain, spleen and heart. 4. Endrin (4 mg/kg) decreased selenium dependent glutathione peroxidase activity in liver and kidney by 64 and 50%, respectively, while small increases were observed in the activities of glutathione reductase and glutathione S-transferase. 5. The toxicity of endrin may be at least in part related to oxidative tissue damage associated with depletion of glutathione and inhibition of glutathione peroxidase activity.     

Influence of acute ethanol administration on hepatic glutathione peroxidase and glutathione transferase activities in the rat

Acute ethanol administration to rats fasted overnight resulted in increased lipid peroxide levels and decreased glutathione content in the liver. In this condition, hepatic glutathione peroxidase activity remained unchanged, whereas glutathione transferase activity was decreased.     

Inhibitory effect of methylmercury on the activity of glutathione peroxidase

Inhibitory effect of methylmercuric chloride (MMC) on the activity of glutathione peroxidase was studied using 100,000g supernatant of the liver homogenate from 10 male SPF Wistar rats in vitro. Marked inhibition of glutathione peroxidase activity was observed between concentrations of 5 × 10^?6 and 5 × 10^?5m MMC, but the activity was hardly inhibited at concentrations less than 5 × 10^?6m MMC; inhibition was almost complete at concentrations greater than 5 × 10^?5m MMC.     

Effect of N-tricyanovinylamines on the level of glutathione in hepatocytes

The effects of N-substituted tricyanovinylamines (N-TCVA; RNHC(CN)=C(CN)2) have been studied on rat hepatocytes and liver mitochondria. Derivatives of N-TCVA act on oxidative phosphorylation as uncouplers, and react with thiols within pH 5.0-8.5. N-Isobutyl-, N-benzyl-, and N-cyclohexyl-TCVA influence the level of GSH and GSSG in isolated hepatocytes. They can act as oxidants, but the level of GSSG increases (about 40%) only if the concentration of N-TCVA is higher than 1 micromol/l. If N-TCVA is added to a final concentration higher than 50 micromol/l a decrease of GSH and GSSG level is observed. Derivatives of N-TCVA also influence the level of GSH and GSSG in mitochondria. At 40-400 micromol/l N-TCVA in the incubation medium the level of GSSG increased and the ratio GSH/GSSG was influenced, but the level of total SH groups did not decrease.     

硒多糖、亚砷酸钠对大鼠肝微粒体酶和GSH-Px等的影响

研究了硒多糖、亚砷酸钠在体内、外对大鼠肝微粒体酶细胞色素Ｐ－４５０、ｂ５、ＮＡＤ（Ｐ）Ｈ－细胞色素Ｃ还原酶、谷胱甘肽硫转移酶（ＧＳＴ）的影响;并通过测定硒多糖、亚砷酸钠对肝谷胱甘肽过氧化物酶（ＧＳＨ－Ｐｘ）和脂质过氧化（ＬＰＯ）的影响,探讨了硒、砷相互作用的机理。结果表明：连续７天腹腔注射０．２ｍｇ／ｋｇ硒多糖,细胞色素Ｐ－４５０、ｂ５的含量、ＧＳＴ的活性降低（Ｐ＜０．０５）;硒多糖明显诱导ＧＳＨ－Ｐｘ的活性,降低脂质过氧化,拮抗亚砷酸钠对ＬＰＯ的作用。亚砷酸钠显著增强肝细胞脂质过氧化（Ｐ＜０．０５）,对ＧＳＨ－Ｐｘ和肝微粒体酶无明显影响     

Effect of some hypoglycemic herbs on the activity of phase I and II drug-metabolizing enzymes in alloxan-induced diabetic rats

Polycyclic aromatic hydrocarbons (PAHs) and N-nitrosamines (NNA) are mainly activated by cytochrome P450s, and their associated enzyme activities such as aryl hydrocarbon (benzo(a)pyrene) hydroxylase (AHH), N-nitrosdimethylamine N-demethylase I (NDMA-dI), NADPH-cytochrome C reductase, and detoxified by glutathione S-transferase (GST) and glutathione (GSH). The present study shows the influence of Cymbopogon proximus (Halfa barr), Zygophyllum coccineum L. (Kammun quaramany), Lupinus albus (Termis) as herbs capable of inducing hypoglycemia on the activity of the above mentioned enzymes in the liver of diabetic rats. Alloxan was administered as a single dose (120 mg/kg body weight) to induce diabetes and the herbs were administered to diabetic rats as repeated doses for 4 weeks. Alloxan-induced diabetes significantly increased the blood glucose level by 93% compared to the control level. On the other hand, repeated-dose treatments of diabetic rats with Cymbopogon proximus and Lupinus albus are more effective than Zygophyllum coccineum in restoring the elevated blood glucose level to the normal level. Alloxan treatment increased the hepatic activity of cytochrome P450, NADPH-cytochrome C reductase, AHH, NDMA-dI, GST and GSH by 112, 122, 82, 99, 64 and 26%, respectively. These herbs decreased the activity of above mentioned enzymes in the liver of diabetic rats compared to alloxan-treated rats. We conclude that alloxan increased the activity of cytochrome P450 system and that such herbs reduced these activities. The toxic effects of PAHs (e.g. benzo(a)pyrene) and NNA (e.g. N-nitrosdimethylamine) could be increased in the liver of diabetic rats through induction of their corresponding bioactivating enzymes. On the other hand, hypoglycemic herbs could alleviate the deleterious effects of these carcinogens in the liver of diabetic rats since these herbs reduced the hepatic content of cytochrome P450 and other associated enzyme activities compared to the diabetic group. Such alterations in the activity of phase I and II drug-metabolizing enzymes should be considered when therapeutic drugs are administered to diabetic patients since most of drugs are metabolized mainly by the cytochrome P450 system.     

Antihyperglycemic and antihyperlipidemic activity of plectranthus amboinicus on normal and alloxan-induced diabetic rats

The present study was undertaken to investigate the antihyperglycemic and antihyperlipidemic effects of ethanol extract of Plectranthus amboinicus in normal and alloxan-induced diabetic rats. Diabetes was induced in Wistar rats by single intraperitoneal administration of alloxan monohydrate (150 mg/kg). Normal as well as diabetic rats were divided into groups (n=6) receiving different treatments. Graded doses (200 mg/kg and 400 mg/kg) of ethanol extract of Plectranthus amboinicus were studied in both normal and alloxan-induced diabetic rats for a period of 15 days. Glibenclamide (600 μg/kg) was used as a reference drug. Oral administration with graded doses of ethanol extract of Plectranthus amboinicus exhibited hypoglycemic effect in normal rats and significantly reduced the peak glucose levels after 120 min of glucose loading. In alloxan-induced diabetic rats, the daily oral treatment with ethanol extract of Plectranthus amboinicus showed a significant reduction in blood glucose. Besides, administration of ethanol extract of Plectranthus amboinicus for 15 days significantly decreased serum contents of total cholesterol, triglycerides whereas HDL-cholesterol, total proteins and calcium were effectively increased. Furthermore, effect of ethanol extract of Plectranthus amboinicus showed profound elevation of serum amylase and reduction of serum lipase. Histology examination showed ethanol extract of Plectranthus amboinicus exhibited almost normalization of damaged pancreatic architecture in rats with diabetes mellitus. Studies clearly demonstrated that ethanol extract of Plectranthus amboinicus leaves possesses hypoglycemic and antihyperlipidemic effects mediated through the restoration of the functions of pancreatic tissues and insulinotropic effect.