Tramadol-induced hepato- and nephrotoxicity in rats: Role of Curcumin and Gallic acid as antioxidants.

Tramadol is an analgesic used to treat moderate to severe pain caused by cancer, osteoarthritis, and other musculoskeletal diseases. Cytochrome P450 system metabolizes tramadol and induces oxidative stress in different organs. Therefore, the present study aims at investigating the changes in the activities and the protein expressions of CYPs isozymes (2E1, 3A4, 2B1/2), antioxidants status, free radicals levels after pretreatment of rats with Curcumin and/or Gallic as single- and/or repeated-doses before administration of tramadol. In repeated-dose treatments of rats with tramadol, the activities of cytochrome P450, cytochrome b5, and NADPH-cytochrome-c-reductase, and the antioxidant enzymes including glutathione reductase, glutathione peroxidase, glutathione S-transferase, catalase, superoxide dismutase, and levels of glutathione were inhibited in the liver and the kidney of rats. Interestingly, such changes caused by tramadol restored to their normal levels after pretreatment of rats with either Curcumin and/or Gallic acid. On the other hand, repeated-dose treatment of rats with tramadol increased the activities of both dimethylnitrosamine N-demethylase I (DMN-dI), and aryl hydrocarbon hydroxylase (AHH) compared to the control group. However, pretreatment of rats with Curcumin and/or Gallic acid prior to administration of tramadol restored the inhibited DMN-dI activity and its protein expression (CYP 2E1) to their normal levels. On the other hand, tramadol inhibited the activity of ethoxycoumarin O-deethylase (ECOD) and suppressed its protein marker expression (CYP2B1/2), whereas Curcumin, Gallic acid and/or their mixture restored such changes to their normal levels. In conclusion, Curcumin and/or Gallic acid alleviated the adverse effects caused by tramadol. In addition, patients should be advice to take Curcumin and/or Gallic acid prior to tramadol treatment to alleviate the hepatic and renal toxicities caused by tramadol

Protective Effects of Essential Oils as Natural Antioxidants against Hepatotoxicity Induced by Cyclophosphamide in Mice.

Clinical application of cyclophosphamide (CP) as an anticancer drug is often limited due to its toxicity. CP is metabolized mainly in the liver by cytochrome P450 system into acrolein which is the proximate toxic metabolite. Many different natural antioxidants were found to alleviate the toxic effects of various toxic agents via different mechanisms. Therefore, the present study aimed at investigating the role of essential oils extracted from fennel, cumin and clove as natural antioxidants in the alleviation of hepatotoxicity induced by CP through assessment of hepatotoxicity biomarkers (AST, ALT, ALP), histopathology of liver tissues as well as other biochemical parameters involved in the metabolism of CP. The data of the present study showed that treatment of male mice with cyclophosphamide (2.5 mg/Kg BW) as repeated dose for 28 consecutive days was found to induce hepatotoxicity through the elevation in the activities of AST, ALT, and ALP. Combined administration of any of these oils with CP to mice partially normalized the altered hepatic biochemical markers caused by CP, whereas administration of fennel, clove or cumin essential oils alone couldn't change liver function indices. Moreover, CP caused histological changes in livers of mice including swelling and dilation in sinusoidal space, inflammation in portal tract and hepatocytes, as well as, hyperplasia in Kuppfer cells. However, co-administration of any of the essential oils with CP alleviated to some extent the changes caused by CP but not as the normal liver. CP was also found to induce free radical levels (measured as thiobarbituric acid reactive substances) and inhibited the activities of superoxide dismutase, glutathione reductase, and catalase as well as activities and protein expressions of both glutathione S-transferase (GSTπ) and glutathione peroxidase. Essential oils restored changes in activities of antioxidant enzymes (SOD, CAT, GR, GST, and GPx) caused by CP to their normal levels compared to control group. In addition, treatment of mice with CP was found to induce the protein expression of CYP 3A4, 2B1/2, 2C6, 2C23. Moreover, the present study showed that essential oils reduced the expression of CYPs 2E1, 3A4 but could not restore the expression of CYP 2C6 and 2C23 compared to CP-treated mice. Interestingly, pretreatment of mice with essential oil of clove was found to restore activities of DMN-dI, AHH, and ECOD which were induced by CP to their normal control levels. It is concluded that EOs showed a marked hepatoprotective effect against hepatotoxicity induced by CP. In addition, co-administration of CP with any of these oils might be used as a new strategy for cancer treatment to alleviate the hepatotoxicity induced by CP

Novel Study on N-Nitrosamines as Risk Factors of Cardiovascular Diseases

Millions of people are exposed daily to N-nitrosamines from different environmental sources. The present study aims at investigating the role of N-nitrosamines in the alteration of homocysteine, lipid profile, oxidative stress, paraoxonase activity, antioxidant enzymes, and free radicals which are important risk factors for CVD. In addition, biomarkers of cardiovascular diseases such as creatine kinase MB activity (CK-MB) and lactate dehydrogenase (LDH) as well as protein expression of both glutathione peroxidase and glutathione S-transferase π isozyme were assayed after treatment of rats with 0.2 mg/kg body weight of N-nitrosodibutylamine (NDBA), N-nitrosoethylbutylamine (NEBA), N-nitrosobutylpropylamine (NBPA), N-nitrosodiethylamine (NDEA), N-nitrosodimethylamine (NDMA), and N-nitrosodiphenylamine (NDPA) as a daily dose for two weeks. LDL levels, paraoxonase activity, reduced glutathione levels, and glutathione reductase activities were increased, whereas HDL levels decreased after treatment of rats with most of N-nitrosamines compared to control group. Moreover, levels of free radicals and catalase activity increased, whereas protein expression of both glutathione peroxidase and glutathione S-transferase decreased after treatment of rats with some N-nitrosamines. The data showed that most N-nitrosamines increased CK-MB and LDH activities. It is concluded that N-nitrosamines increased levels of free radicals, and decreased the activity of antioxidant enzymes which may consequently increase the incidence of CVDs

Novel Study on N-Nitrosamines as Risk Factors of Cardiovascular Diseases

Millions of people are exposed daily to N-nitrosamines from different environmental sources. The present study aims at investigating the role of N-nitrosamines in the alteration of homocysteine, lipid profile, oxidative stress, paraoxonase activity, antioxidant enzymes, and free radicals which are important risk factors for CVD. In addition, biomarkers of cardiovascular diseases such as creatine kinase MB activity (CK-MB) and lactate dehydrogenase (LDH) as well as protein expression of both glutathione peroxidase and glutathione S-transferase isozyme were assayed after treatment of rats with 0.2 mg/kg body weight of N-nitrosodibutylamine (NDBA), N-nitrosoethylbutylamine (NEBA), N-nitrosobutylpropylamine (NBPA), N-nitrosodiethylamine (NDEA), N-nitrosodimethylamine (NDMA), and N-nitrosodiphenylamine (NDPA) as a daily dose for two weeks. LDL levels, paraoxonase activity, reduced glutathione levels, and glutathione reductase activities were increased, whereas HDL levels decreased after treatment of rats with most of N-nitrosamines compared to control group. Moreover, levels of free radicals and catalase activity increased, whereas protein expression of both glutathione peroxidase and glutathione S-transferase decreased after treatment of rats with some N-nitrosamines. The data showed that most N-nitrosamines increased CK-MB and LDH activities. It is concluded that N-nitrosamines increased levels of free radicals, and decreased the activity of antioxidant enzymes which may consequently increase the incidence of CVDs

Major components of clove essential oil.

<p>Major components of clove essential oil.</p

Major components of cumin essential oil.

<p>Major components of cumin essential oil.</p

Major components of fennel essential oil.

<p>Major components of fennel essential oil.</p