Cytochrome P450-dependent mixed-function oxidase and glutathione S-transferase activities in spontaneous obesity-diabetes

doi:10.1016/0006-2952(92)90724-W

Biochemical Pharmacology

Volume 43, Issue 8, 15 April 1992, Pages 1868-1871

https://doi.org/10.1016/0006-2952(92)90724-W Get rights and content

Abstract

The effect of non-insulin-dependent diabetes on the hepatic microsomal cytochrome P450-dependent mixed-function oxidase system and on cytosolic glutathione S-transferase activity was determined using the spontaneously obese-diabetic (ob/ob) mouse model. The activities of the xenobiotic-metabolizing cytochrome P450 proteins were monitored by the use of chemical probes. Non-insulin-dependent diabetes did not influence the hepatic metabolism of substrates associated with the P450 I, IIB, IIE, III and IV families of cytochromes. In contrast, cytosolic glutathione S-transferase activity was markedly reduced and glutathione levels were significantly lowered. These findings raise the possibility that patients suffering from this disease may be more susceptible to chemicals that rely on glutathione conjugation for their deactivation.

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Therefore, it could be suggested that the antioxidant defence system is reinforced to face oxidative stress, as previously shown in diabetic and high-fat fed rats (Aksoy, Vural, Sabuncu, & Aksoy, 2003; Alezandro, Granato, & Genovese, 2013; Shrivastava, Chaturvedi, Singh, Saxena, & Bhatia, 2013). Interestingly, the detoxifying enzyme GST has been proved to decrease in diabetic mice (Barnett, Abbott, Bailey, Flatt, & Ioannides, 1992), which has been related to a diminished hepatic enzymatic expression and activity because of lower insulin stimulation during hepatic resistance (Kim, Woodcroft, & Novak, 2003). Indeed, insulin resistance was partly prevented in ZDF-Ca rats when compared to ZDF-C animals, according to insulin sensitivity indexes AUC glucose/AUC insulin ratio and HOMA-IR (Table 2), but this seems not to be enough to restore the hepatic GST activity.
Chronic hyperglycemia in diabetes is associated with oxidative stress-mediated tissue damage. The present study is aimed to explore the role of a cocoa-enriched diet in ameliorating the oxidative stress-induced damage in the liver of young type 2 diabetic Zucker diabetic fatty (ZDF) rats. Male ZDF rats were fed a control or cocoa-rich diet (10%), and Zucker Lean (ZL) animals received the control diet. ZDF rats fed with cocoa (ZDF-Ca) decreased body weight gain, glucose and insulin levels, and improved glucose tolerance and insulin resistance. Cocoa diet further reduced reactive oxygen species (ROS) levels and carbonyl content in the liver of ZDF animals. The diminished activity of superoxide dismutase (SOD) and the enhanced activity of heme oxygenase (HO-1) in ZDF-C were returned to ZL values upon cocoa administration. Cocoa did not restore the decreased glutathione-S-transferase (GST) activity in both ZDF groups in comparison to ZL rats. Glutathione (GSH) content and activities of glutathione peroxidase (GPx), glutathione reductase (GR) and catalase (CAT) remained unaltered among all animal groups. Moreover, cocoa-rich diet suppressed total and phosphorylated nuclear factor erythroid-derived 2-like 2 (Nrf2), as well as p65-nuclear factor-kappaB (NF-ĸB) enhanced levels observed in ZDF rats. The results indicate that cocoa protects the hepatocytes by improving the antioxidant competence in the liver of young type 2 diabetic ZDF rats.
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The present study showed that the total hepatic GST activity increased in the obese–diabetic mice, and this parallels reported increases in glutathione conjugation in obese humans (Abernethy and Greenblatt, 1986; Roe et al., 1999; Kim et al., 2003). However, other animal studies using spontaneous obese–diabetic male mice have decreased (Barnett et al., 1992; Roe et al., 1999) or unchanged GST activities (Rouer et al., 1981; Kim et al., 2003). The differences in GST activity reported throughout the literature is likely due to different methods of inducing obesity–diabetes, and the status of the disease in the animals.
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Male C57BL/6J mice were randomized to 4 groups and fed standard (10% kcal from fat) diet with or without bamboo extract supplementation at a dose of 10 gram per kilogram diet (n = 10 and n = 9, respectively), or high fat (45% kcal from fat) diet with or without bamboo extract (n = 8 and N = 7, respectively). The dietary treatment lasted for 6 months. Subsequently, the activities and expression of the major Phase I and II hepatic biotransformation enzymes were assessed in subcellular fractions from murine livers.
Three groups of mice, lean bamboo extract-supplemented, obese/diabetic, and bamboo extract-supplemented obese/diabetic, showed greater activities of cytochromes P450 1a2 and 3a11 compared to control but no changes in the expression level of these proteins. For Phase II enzymes, bamboo extract supplementation in lean mice caused decreased glutathione-S-transferase activity (−12%) and greater uridine diphosphate glucuronosyltransferase activity (+46%), but had no effect on sulfotransferase activity. Conversely, the obese/diabetic condition itself increased glutathione-S-transferase and uridine diphosphate glucuronosyltransferase activities, but decreased total sulfotransferase activity and sulfotransferase 2a1 expression.
Bamboo extract and obesity/diabetes show significant independent effects on hepatic biotransformation as well as interaction effects in mice. These changes may alter the clearance of endo- and xenobiotics, including bamboo extract itself, hence this effect should be carefully considered in the medicinal application of bamboo extract as it has potential to alter its own metabolism and that of other medications concurrently administered to obese diabetic patients.
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The peroxisome proliferator-activated receptor-α (PPARα) regulates lipid homeostasis, particularly in the liver. This study was aimed at elucidating the relationship between hepatosteatosis and oxidative stress during fasting. Fasted Ppara-null mice exhibited marked hepatosteatosis, which was associated with elevated levels of lipid peroxidation, nitric oxide synthase activity, and hydrogen peroxide accumulation. Total glutathione (GSH), mitochondrial GSH, and the activities of major antioxidant enzymes were also lower in the fasted Ppara-null mice. Consequently, the number and extent of nitrated proteins were markedly increased in the fasted Ppara-null mice, although high levels of protein nitration were still detected in the fed Ppara-null mice while many oxidatively modified proteins were only found in the fasted Ppara-null mice. However, the role of inflammation in increased oxidative stress in the fasted Ppara-null mice was minimal based on the similar levels of tumor necrosis factor-α change in all groups. These results with increased oxidative stress observed in the fasted Ppara-null mice compared with other groups demonstrate a role for PPARα in fasting-mediated oxidative stress and that inhibition of PPARα functions may increase the susceptibility to oxidative damage in the presence of another toxic agent.
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Short communicationCytochrome P450-dependent mixed-function oxidase and glutathione S-transferase activities in spontaneous obesity-diabetes

Abstract

Pharmacol Ther

Chem Biol Interact

Biochem Pharmacol

Toxicol Appl Pharmacol

Arch Biochem Biophys

J Biol Chem

J Biol Chem

J Biol Chem

Methods Enzymol

J Biol Chem

J Biol Chem

J Biol Chem

J Clin Chim Acta

J Biol Chem

Biochem Pharmacol

Biochim Biophys Acta

Biochem Pharmacol

The cytochrome P450I gene family of microsomal hemoproteins and their role in the metabolic activation of chemicals

Drug Metab Rev

Short communication
Cytochrome P450-dependent mixed-function oxidase and glutathione S-transferase activities in spontaneous obesity-diabetes