Oxidative stress as a mechanism underlying sulfasalazine-induced toxicity

Introduction: Sulfasalazine (SASP) is a drug commonly used in the treatment of inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease (CD) and rheumatoid arthritis (RA). A high incidence of side effects limits therapy with this drug. Getting a wider knowledge of drug pharmacology, indications and side effects is essential to ensure the best possible clinical care, minimizing toxicity and inappropriate use.

Areas covered: This paper gives an overview of recent research about SASP and its main adverse effects, highlighting the mechanisms underlying them. To give an overview and comment on the data available so far on this topic, relevant literature was identified using a PubMed search of articles published up to December 2009. Search terms included: ‘sulfasalazine’, ‘oxidative stress, ‘renal effects’, ‘hepatotoxicity’ and ‘male fertility’. Original papers were reviewed and relevant citations from these articles were also considered.

Expert opinion: Although SASP and 5-aminosalicylic acid also scavenge ROS, which may account for some of their anti-inflammatory properties, the reaction with ROS may also generate toxic free radicals; hence, the ability of other antioxidants to suppress the toxicity of SASP in vivo. Further investigations, particularly about SASP mechanism, are still needed.     

Oxidative stress as a mechanism underlying sulfasalazine-induced toxicity

INTRODUCTION: Sulfasalazine (SASP) is a drug commonly used in the treatment of inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease (CD) and rheumatoid arthritis (RA). A high incidence of side effects limits therapy with this drug. Getting a wider knowledge of drug pharmacology, indications and side effects is essential to ensure the best possible clinical care, minimizing toxicity and inappropriate use. AREAS COVERED: This paper gives an overview of recent research about SASP and its main adverse effects, highlighting the mechanisms underlying them. To give an overview and comment on the data available so far on this topic, relevant literature was identified using a PubMed search of articles published up to December 2009. Search terms included: 'sulfasalazine', 'oxidative stress, 'renal effects', 'hepatotoxicity' and 'male fertility'. Original papers were reviewed and relevant citations from these articles were also considered. EXPERT OPINION: Although SASP and 5-aminosalicylic acid also scavenge ROS, which may account for some of their anti-inflammatory properties, the reaction with ROS may also generate toxic free radicals; hence, the ability of other antioxidants to suppress the toxicity of SASP in vivo. Further investigations, particularly about SASP mechanism, are still needed.     

Enhanced oxidative stress in hypertrophic cardiomyopathy

Elevated plasma levels of inflammation and endothelial dysfunction markers have been reported in patients with hypertrophic cardiomyopathy (HCM). The aim of the current study was to determine whether HCM is associated with enhanced oxidative stress. We enrolled 54HCMpatients with sinus rhythm, including 21 subjects with a left ventricular outflow tract (LVOT) obstruction (gradient ≥ 30 mmHg), and 54 age- and sex-matched controls without cardiovascular diseases. Serum levels of 8-isoprostaglandin F_2α (8-iso-PGF_2α), a stable marker of oxidative stress, were determined.Serum 8-iso-PGF_2α levels were elevated in HCM patients compared with controls (35.4 ± 10.2 vs. 29.9 ± 9.9 pg/ml, p < 0.001). Patients with obstructiveHCMdisplayed higher 8-iso-PGF_2α levels compared with the non-obstructiveHCMsubgroup (41.6 ± 12.7 vs. 31.4 ± 5.4 pg/ml, p < 0.0001). Both anatomic (mitral-septal distance) and hemodynamic (subaortic gradient) indexes of LVOT obstruction, but not other echocardiographic variables, correlated with 8-iso-PGF_2α levels (r = –0.43; p < 0.05 and r = 0.39; p < 0.05, respectively).This study is the first to show that HCM is characterized by enhanced oxidative stress as evidenced by higher 8-iso-PGF_2α, which achieves its highest values in the presence of LVOT obstruction in HCM patients.     

Lipoic acid as a potential therapy for chronic diseases associated with oxidative stress

alpha-Lipoic acid (LA), a naturally occurring dithiol compound, has long been known as an essential cofactor for mitochondrial bioenergetic enzymes. Aside from its enzymatic role, in vitro and in vivo studies suggest that LA also acts as a powerful micronutrient with diverse pharmacologic and antioxidant properties. Pharmacologically, LA improves glycemic control, polyneuropathies associated with diabetes mellitus, and effectively mitigates toxicities associated with heavy metal poisoning. As an antioxidant, LA directly terminates free radicals, chelates transition metal ions (e.g. iron and copper), increases cytosolic glutathione and vitamin C levels and prevents toxicities associated with their loss. These diverse actions suggest that LA acts by multiple mechanisms both physiologically and pharmacologically, many of which are only now being explored. Herein, we review the known biochemical properties of LA with particular reference to how LA may be an effective agent to ameliorate certain pathophysiologies of many chronic diseases.     

Evidences for oxidative stress in essential hypertension

Aim  

This study explores the degree of oxidative stress in essential arterial hypertension (EAH). Even oxidative stress appears as one of several metabolic abnormalities involved in essential hypertension, it remains uncertain whether is primary or secondary. However measurement of the main oxidant may be useful in order to recognize and monitor oxidative stress.     

Embryonic oxidative stress as a mechanism of teratogenesis with special emphasis on diabetic embryopathy

Reactive oxygen species (ROS) are involved in the etiology of numerous diseases including cardio-vascular diseases and diabetes mellitus. There is evidence that several teratogens affect the developing embryo by increasing its oxidative stress and, because of its relatively weak antioxidant defense, especially at the early stages of organogenesis, result in severe embryonic damage. This mechanism seems to operate in diabetes-induced embryonic damage as well as in the mechanism of teratogenicity caused by ionizing radiation, hypoxia, alcohol and cocaine use and cigarette smoking. We studied the role of oxidative stress in diabetic induced embryopathy, both in vivo and in vitro. Under diabetic condition there was a significant decrease in the activity of endogenous antioxidant enzymes and of vitamins C and E in the embryos and their yolk sacs. The lowest activity was observed in the malformed experimental embryos when compared to experimental embryos without anomalies. Similar results were obtained in the Cohen diabetic rats, where the diabetic prone (CDs) rats were unable to increase their antioxidant enzyme activity in spite of the diabetes. Studies performed by other investigators show similar results. Human and animal studies show that the main mechanism of fetal damage induced by high levels of ionizing irradiation, cocaine and alcohol abuse, hypoxia and cigarette smoking is also by increased embryonic oxidative stress. Similarly, several drugs exert their teratogenic activity via embryonic oxidative stress. Abnormal placentation may also cause enhanced placental oxidative stress, resulting in embryonic death, preeclampsia or congenital anomalies. Inability of the developing embryo to cope with that stress may result in embryonic death and/or congenital anomalies. Animal studies also show that a variety of antioxidants are effective in decreasing the damaging effects of heightened oxidative stress induced by teratogens. Effective antioxidants, which might also be of clinical use, include vitamins C and E, carotenoids, folic acid, as well as synthetic products. Appropriate clinical studies with antioxidants in pregnancies of high risk to develop oxidative stress are needed, since non-toxic antioxidants might prove an efficient and inexpensive way to reduce the rate of some serious and sometimes fatal congenital anomalies.     

Liver microsomal biotransformation of nitro-aryl drugs: mechanism for potential oxidative stress induction

Toxic effects of several nitro-aryl drugs are attributed to the nitro-reduction that may be suffered in vivo, a reaction that may be catalysed by different reductases. One of these enzymes is NADPH-cytochrome P450 reductase, which belongs to the cytochrome P450 oxidative system mainly localized in the endoplasmic reticulum of the hepatic cell. This system is responsible for the biotransformation of oxidative lipophilic compounds, so that oxidative and reductive metabolic pathways of lipophilic nitro-aryl drugs can take place simultaneously. Because of the affinity of nitro-aryl drugs (xenobiotics) for the endoplasmic reticulum, we propose this subcellular organelle as a good biological system for investigating the toxicity induced by the biotransformation of these or another compounds.In this work we used rat liver microsomes to assess the oxidative stress induced by nitro-aryl drug biotransformation. Incubation of microsomes of rat liver with nifurtimox and nitrofurantoin in the presence of NADPH induced lipoperoxidation, UDP-glucuronyltransferase activation and an increase in the basal microsomal oxygen consumption. Nitro-aryl-1,4-dihydropyridines did not elicit these prooxidant effects; furthermore, they inhibited lipoperoxidation and oxygen consumption induced by Fe3+/ascorbate. Nifurtimox and nitrofurantoin modified the maximum absorption of cytochrome P450 oxidase and inhibited p-nitroanisole O-demethylation, an oxidative reaction catalysed by the cytochrome P450 system, signifying that oxidation may proceed in a similar way to that described for nitro-aryl-1,4-dihydropyridines. Thus the balance between lipophilic nitro-aryl drug oxidation and reduction may be involved in the potential oxidative stress induced by biotransformation.     

The role of oxidative stress in renovascular hypertension

1. There is mounting evidence that increased oxidative stress and sympathetic nerve activity play important roles in renovascular hypertension. In the present review, we focus on the importance of oxidative stress in two distinct populations of neurons involved with cardiovascular regulation: those of the rostral ventrolateral medulla (RVLM) and those of the paraventricular nucleus of the hypothalamus (PVN) in the maintenance of sympathoexcitation and hypertension in two kidney–one clip (2K1C) hypertensive rats. Furthermore, the role of oxidative stress in the clipped kidney is also discussed. 2. In the studies reviewed in this article, it was found that hypertension and renal sympathoexcitation in 2K1C rats were associated with an increase in Angiotensin II type one receptor (AT₁) expression and in oxidative markers within the RVLM, PVN and in the clipped kidneys of 2K1C rats. Furthermore, acute or chronic anti‐oxidant treatment decreased blood pressure and sympathetic activity, and improved the baroreflex control of heart rate and renal sympathetic nerve activity in 2K1C rats. Tempol or vitamin C administration in the RVLM, PVN or systemically all reduced blood pressure and renal sympathetic activity. Cardiovascular improvement in response to chronic anti‐oxidant treatment was associated with a downregulation of AT₁ receptors, as well as oxidative markers in the central nuclei and clipped kidney. 3. The data discussed in the present review support the idea that an increase in oxidative stress within the RVLM, PVN and in the ischaemic kidney plays a major role in the maintenance of sympathoexcitation and hypertension in 2K1C rats.     

Alteration of hepatic cells glucose metabolism as a non-cholinergic detoxication mechanism in counteracting diazinon-induced oxidative stress

The aim of this study was to evaluate effects of acute exposure to various doses of diazinon, a widely used synthetic organophosphorus (OP) insecticide on plasma glucose, hepatic cells key enzymes of glycogenolysis and gluconeogenesis, and oxidative stress in rats. Diazinon was administered by gavage at doses of 15, 30 and 60 mg/ kg. The liver was perfused and removed under anaesthesia. The activities of glycogen phosphorylase (GP), phosphoenolpyruvate carboxykinase (PEPCK), thiobarbituric acid reactive substances (TBARS) and total antioxidant capacity (TAC) were analysed in liver homogenate. Administration of diazinon (15, 30 and 60 mg/kg) increased plasma glucose concentrations by 101.43% (P = 0.001), 103.68% (P = 0.000) and 160.65% (P = 0.000) of control, respectively. Diazinon (15, 30 and 60 mg/kg) increased hepatic GP activity by 43.5% (P = 0.05), 70.3% (P = 0.00) and 117.2% (P = 0.02) of control, respectively. In addition, diazinon (30 and 60 mg/kg) increased hepatic PEPCK by 77.3% (P = 0.000) and 93.5% (P = 0.000) of control, respectively. Diazinon (30 and 60 mg/kg) decreased liver TAC by 38% (P = 0.046) and 48% (P = 0.000) of control, respectively. Also diazinon (30 and 60 mg/kg) increased hepatic cell liver lipid peroxidation by 77% (P = 0.05) and 280% (P = 0.000) of control. The correlations between plasma glucose and hepatic cells TBARS (r2 = 0.537, P = 0.02), between plasma glucose and ChE activity (r2 = 0.81, P = 0.049) and between plasma glucose and hepatic cells GP activity (r2 = 0.833, P = 0.04) were significant. It is concluded that the liver cells are a site of toxic action of diazinon. Diazinon increases glucose release from liver into blood through activation of glycogenolysis and gluconeogenesis as a detoxication non-cholinergic mechanism to overwhelm diazinon-induced toxic stress. The results are in accordance with the hypothesis that OPs are a predisposing factor of diabetes.     

Comparison of in vitro and in utero ethanol exposure on indices of oxidative stress

Prenatal ethanol exposure produces neural tube defects and growth retardation in experimental animals. Because ethanol's teratogenic effects may involve oxidative stress and effects may differ in vitro and in utero, glutathione, cysteine and ATP were evaluated in gestational day 10 rat conceptuses exposed to ethanol. Cultured embryos exposed to ethanol (1.5 or 3.0 mg/mL) maintained a concentration-dependent decrease in glutathione of 21 or 35%, respectively, at 6 h; visceral yolk sac (VYS) glutathione (GSH) decreased by 22 or 18%, respectively, at 3 h. Maternal ethanol exposure (4.5 g/kg) decreased glutathione by 30% in embryos and VYSs at 3 h, but values rebounded. Cultured embryonic cysteine decreased after 30 min by 42% with both doses and after 6 h by 32 or 38% with 1.5 or 3.0 mg/mL, respectively. Ethanol (1.5 mg/mL) increased VYS cysteine by 35% after 30 min. In utero ethanol exposure decreased embryonic cysteine by 58% at 3 h. Ethanol (1.5 mg/mL) decreased adenosine triphosphate (ATP) by 30-60% in embryos and VYSs at 30 min. After 6 h, embryonic ATP decreased by 41 and 30% with 1.5 and 3.0 mg/mL, respectively, while VYS ATP decreased by 38% with 1.5 mg/mL. In utero ethanol exposure decreased ATP by 31% at 3 h in VYSs. While decreases in GSH and cysteine were evident earlier in utero than in vitro, values returned to control suggesting embryos exposed in utero respond rapidly to chemical-induced oxidative stress due to maternal protective mechanisms. Differences between in vitro and in utero responses to ethanol have important implications for interpretation of in vitro developmental studies.     

Statins as potential treatment for cholesterol gallstones: an attempt to understand the underlying mechanism of actions

Introduction: Statin therapy is widely used across the globe for the treatment and prevention of cardiovascular disease (CVD). It is well established that statin therapy is associated with significant decreases in low-density lipoprotein cholesterol (LDL-C) and plasma cholesterol levels. Cholesterol gallstones are a common problem, resulting in hospital admission and surgery, throughout western healthcare systems.

Areas covered: This review describes the mechanisms, and addresses the potential, for statins to be used as a treatment for gallstones. Medline was searched for the risk factors and treatment of cholesterol gallstones.

Expert opinion: Obesity, metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), insulin resistance and high-fat diets (unsaturated fats) rich in cholesterol are all associated risk factors for cholesterol gallstones. In view of the high prevalence of cholesterol gallstones, there is an urgent need to understand whether pharmacological therapies can be harnessed for the treatment of cholesterol gallstones. Gallstones are shown to be associated with an increased risk, not only of mortality, but also of CVD. Statins, widely used in prevention of CVD and hypercholesteremia, have been shown to dissolve cholesterol gallstones in animal models and human studies, highlighting the potential for a pharmacological therapy for gallstones. More studies are required to understand the role of statins in the treatment of gallstones and for comparison with current treatment strategies.     

Implications of oxidative stress and homocysteine in the pathophysiology of essential hypertension

The present review examines the clinical and experimental data to support the view that homocysteine and oxidative stress, two alternative risk factors of vascular disease, may play a role in the pathogenesis of primary or essential hypertension. Although the precise mechanism of this disease has not been elucidated, it may be related to impairment of vascular endothelial and smooth muscle cell function. Thus, the occurrence of endothelial dysfunction could contribute to alterations of the endothelium-dependent vasomotor regulation. Hyperhomocysteinemia limits the bioavailability of nitric oxide, increases oxidative stress, stimulates the proliferation of vascular smooth muscle cells, and alters the elastic properties of the vascular wall. The link between oxidative stress and hyperhomocysteinemia is also biologically plausible, because homocysteine promotes oxidant injury to the endothelium. Cumulated evidence suggests that the diminution of oxidative stress with antioxidants or the correction of hyperhomocysteinemia with vitamins-B plus folic acid, could be useful as an adjuvant therapy for essential hypertension. Further studies involving long-term trials could help to assess the tolerability and efficacy of the use of these therapeutic agents.     

Statins as potential treatment for cholesterol gallstones: an attempt to understand the underlying mechanism of actions

INTRODUCTION: Statin therapy is widely used across the globe for the treatment and prevention of cardiovascular disease (CVD). It is well established that statin therapy is associated with significant decreases in low-density lipoprotein cholesterol (LDL-C) and plasma cholesterol levels. Cholesterol gallstones are a common problem, resulting in hospital admission and surgery, throughout western healthcare systems. AREAS COVERED: This review describes the mechanisms, and addresses the potential, for statins to be used as a treatment for gallstones. Medline was searched for the risk factors and treatment of cholesterol gallstones. EXPERT OPINION: Obesity, metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), insulin resistance and high-fat diets (unsaturated fats) rich in cholesterol are all associated risk factors for cholesterol gallstones. In view of the high prevalence of cholesterol gallstones, there is an urgent need to understand whether pharmacological therapies can be harnessed for the treatment of cholesterol gallstones. Gallstones are shown to be associated with an increased risk, not only of mortality, but also of CVD. Statins, widely used in prevention of CVD and hypercholesteremia, have been shown to dissolve cholesterol gallstones in animal models and human studies, highlighting the potential for a pharmacological therapy for gallstones. More studies are required to understand the role of statins in the treatment of gallstones and for comparison with current treatment strategies.     

The ribotoxic stress response as a potential mechanism for MAP kinase activation in xenobiotic toxicity.

The article highlighted in this issue is "Vomitoxin-InducedCyclooxygenase-2 Gene Expression in Macrophages Mediated byActivation of ERK and p38 but Not JNK Mitogen-Activated ProteinKinases," by Yuseok Moon and James J. Pestka (pp. 373–382).     

The cytotoxic mechanism of glyoxal involves oxidative stress

Glyoxal is a reactive alpha-oxoaldehyde that is a physiological metabolite formed by lipid peroxidation, ascorbate autoxidation, oxidative degradation of glucose and degradation of glycated proteins. Glyoxal is capable of inducing cellular damage, like methylglyoxal (MG), but may also accelerate the rate of glycation leading to the formation of advanced glycation end-products (AGEs). However, the mechanism of glyoxal cytotoxicity has not been precisely defined. In this study we have focused on the cytotoxic effects of glyoxal and its ability to overcome cellular resistance to oxidative stress. Isolated rat hepatocytes were incubated with different concentrations of glyoxal. Glyoxal by itself was cytotoxic at 5mM, depleted GSH, formed reactive oxygen species (ROS) and collapsed the mitochondrial membrane potential. Glyoxal also induced lipid peroxidation and formaldehyde formation. Glycolytic substrates, e.g. fructose, sorbitol and xylitol inhibited glyoxal-induced cytotoxicity and prevented the decrease in mitochondrial membrane potential suggesting that mitochondrial toxicity contributed to the cytotoxic mechanism. Glyoxal cytotoxicity was prevented by the glyoxal traps d-penicillamine or aminoguanidine or ROS scavengers were also cytoprotective even when added some time after glyoxal suggesting that oxidative stress contributed to the glyoxal cytotoxic mechanism.     

Inhibitory mechanism against oxidative stress of caffeic acid

The purpose of this article is to summarize the reported antioxidant activities of a naturally abundant bioactive phenolic acid, caffeic acid (CA, 3,4-dihydroxycinnamic acid), so that new avenues for future research involving CA can be explored. CA is abundantly found in coffee, fruits, vegetables, oils, and tea. CA is among the most potential and abundantly found in nature, hydroxycinnamic acids with the potential of antioxidant behavior. Reactive oxygen species produced as a result of endogenous processes can lead to pathophysiological disturbances in the human body. Foods containing phenolic substances are a potential source for free radical scavenging; these chemicals are known as antioxidants. This review is focused on CA’s structure, availability, and potential as an antioxidant along with its mode of action. A brief overview of the literature published about the prooxidant potential of caffeic acid as well as the future perspectives of caffeic acid research is described. CA can be effectively employed as a natural antioxidant in various food products such as oils.     

Sildenafil attenuates oxidative stress and endothelial dysfunction in lead-induced hypertension

Lead (Pb) reduces NO bioavailability, impairs the antioxidant system, and increases the generation of reactive oxygen species (ROS). Pb-induced oxidative stress may be responsible for the associated endothelial dysfunction. Sildenafil has shown nitric oxide (NO)-independent action, including antioxidant effects. Therefore, we examined the effects of sildenafil on oxidative stress, reductions of NO and endothelial dysfunction in Pb-induced hypertension. Wistar rats were distributed into three groups: Pb, Pb + sildenafil and Sham. Blood pressure and endothelium-dependent vascular function were recorded. We also examined biochemical determinants of lipid peroxidation and antioxidant function. ROS levels, NO metabolites and NO levels in human umbilical vein endothelial cells (HUVECs) were also evaluated. Sildenafil prevents impairment of endothelium-dependent NO-mediated vasodilation and attenuates Pb-induced hypertension, reduces ROS formation, enhances superoxide dismutase (SOD) activity and antioxidant capacity in plasma and increases NO metabolites in plasma and HUVECs culture supernatants, while no changes were found on measurement of NO released from HUVECs incubated with plasma of the Pb and Pb + sildenafil groups compared with the sham group. In conclusion, sildenafil protects against ROS-mediated inactivation of NO, thus preventing endothelial dysfunction and attenuating Pb-induced hypertension, possibly through antioxidant effects.     

Oxidative stress as an underlying mechanism of anticancer drugs cytotoxicity on human red blood cells' membrane

The aim of this study is to investigate the direct in vitro effects of anticancer drugs on red blood cells (RBCs) and to explore the underlying mechanism, mainly by measuring RBCs oxidative stress (OS) status. After RBCs direct contact with fourteen (14) anticancer drugs, several parameters were assessed including: cellular turbidity, methemoglobin (metHb) generation, released Hb and Hb stability. Moreover, intracellular Hb, considered as new molecular target of anticancer drugs, was quantified inside RBCs. MDA level, the main biomarker of OS, was simultaneously measured. The cellular turbidity reveled severe (docetaxel “TXT”, 0.03 ± 0.002), moderate (methotrexate “MTX”, 0.49 ± 0.009), or none (5-fluorouracil “5-FU”, 0.76 ± 0.029) membrane cytotoxicity (MC). An inverse relationship between cell concentration, released Hb and metHb content was obtained. High metHb generation, revealing intense OS, was also mostly expressed in paclitaxel “TXL” and etoposide “VP16”. Further, epirubicin “EPI” and “TXT” induced important oxidation of membrane lipids with 0.32 ± 0.014 and 0.26 ± 0.004, respectively. Also, MTX (0.17 ± 0.006) and doxorubicin “DOX” (0.32 ± 0.034) affected significantly Hb stability by a direct contact with molecule. These findings demonstrated that anticancer drugs have the ability to induce membrane damages by the exacerbation of OS through membrane lipid peroxidation and Hb oxidation even inside RBCs.     

Maternal nicotine exposure and fetal programming of vascular oxidative stress in adult offspring

Despite the well-known harmful effects, many women continue to smoke throughout pregnancy. Consequently, nicotine replacement therapy (NRT) - which has been developed as a pharmacotherapy for smoking cessation - has been used as an alternative to smoking during pregnancy. However, like cigarette smoking, NRT results in biologically significant levels of nicotine crossing the placenta, leading to both fetal and neonatal exposure to nicotine, and yet, NRT safety during pregnancy has not been extensively evaluated. There is now evidence from studies in rats that maternal nicotine exposure throughout gestation results in fetal programming of vascular oxidative stress in the offspring during adulthood. This phenomenon involves vascular dysfunction mediated by reactive oxygen species in association with decreased superoxide dismutase activity and increased Nox2-NADPH oxidase expression in the vascular wall. If this phenomenon also occurs in humans, either smoking or NRT use during pregnancy may represent a novel risk factor for the unborn that results in accelerated cardiovascular disease in their adulthood.