Inhibitory Effect of Dimethyl Sulfoxide (DMSO) on Necrosis and Oxidative Stress Caused by D-Galactosamine in the Rat Liver

Abstract

Summary D -Galactosamine ( D -Galn: 300 mg/kg) was intraperitoneally administered to rats. After 6 h the activity of plasma GOT and GPT was significantly higher than that of the control group and plasma GOT and GPT activities increased thereafter. These results indicated that the necrotic process was initiated at about 6 h and developed thereafter. With coadministration of DMSO (1 h before administration of D -Galn: 2.5 mL/kg, oral), plasma GOT and GPT were significantly lower, showing that DMSO inhibited the necrotic action of DGaln. After 6-24 h of D -Galn administration, the hepatic level of vitamin C, the most sensitive indicator of oxidative stress, decreased significantly, indicating that oxidative stress was significantly enhanced 6 h after D -Galn intoxication and thereafter. DMSO significantly restored the liver vitamin C level 24 h after D -Galn injection, demonstrating that DMSO effectively ameliorated the oxidative stress caused by D -Galn, resulting in the prevention of necrosis of the liver. Phosphorylated JNK and phospho-ERK were significantly increased transiently 6-12 h after treatment with D -Galn. These results indicated that oxidative stress and the activation of JNK took place almost simultaneously. Phosphorylated p38 MAPK was not changed and DMSO treatment did not affect the change of these MAPKs by D -Galn. Key Words DMSO, galactosamine, MAPK, oxidative stress, vitamin C Hepatoprotection remains one of the major challenges in nutritional and clinical therapy to limit liver injuries such as chronic hepatitis and fulminant hepatic failure. To study this issue more effectively, experimental methods are necessary to cause effective hepatic failure. Chemical toxins such as D -galactosamine ( D -Galn) ( 1 ), thioacetamide ( 2 ), and carbon tetrachloride ( 3 ) have been used for this purpose. D -Galn is known as a toxin causing necrosis of the liver by UTP depletion and inhibition of protein synthesis ( 4 ). Recently, we reported that radical reactions were caused by D -Galn in the early stage based on a decrease in vitamin C ( 1 ), resulting in necrosis. In chemically induced hepatitis ( 1-3 ), liver vitamin C was firstly consumed by oxidative stress, indicating that vitamin C was the most sensitive indicator of oxidative stress ( 5 ).Antioxidants in foods are therefore expected to protect the liver from oxidative stress caused by these chemicals. To survey the antioxidative effect of food factors, it is necessary to investigate effects of a known antioxidant on the liver. Only limited studies are available and DMSO is reported to function as an antioxidant in cultured hepatocytes ( 6 ) as well as in the rat liver under thioacetamide intoxication (6)(7)(8). In this report, we have attempted to investigate whether DMSO functions in vivo as an antioxidant and protects against necrosis of the liver caused by D -Galn even in a pharmacological dose. For this purpose we evaluated oxidative stress using hepatic vitamin C level and activation profiles of the three major subclasses of the MAPK (mitogen a...

Hepatoprotective Effect of Curcumin and Capsaicin against Lipopolysaccharide Induced Liver Damage in Mice

“…The cascade of activities initiated by LPS intoxication leads to disruption of structural integrity of the hepatic cell membrane and release of SGOT, SGPT, ALP, lactate dehydrogenase (LDH) and alkaline phosphatase (AP) hepatic non-specific enzymes into the blood stream from the affected, necrotic and dead hepatocytes and possible hepatic dysfunction manifested by increased serum total bilirubin, thus producing signs of hepatotoxicity. 26,27 In the present study, the observation of elevated level of serum SGOT, SGPT, ALP and total bilirubin in the group of mice treated with LPS alone is consistent with these reports and might explain the inflammation manifested in liver. Earlier reports state that supplementation of natural antioxidants were proven to be an excellent prevention strategy for many diseases, including diabetes liver injury, liver fibrosis, cancer and ageing.…”

Protective role of c-Jun N-terminal kinase 2 in acetaminophen-induced liver injury

“…Potential limitations of these studies, as acknowledged by the investigators [21,22] is that JNK inhibitors may not be specific and as reported can affect other signaling events that could lead to the misinterpretation of results [36][37][38][39]. Further, some of the JNK inhibitors were dissolved in vehicles containing DMSO [14,21] and polyethylene glycol [22,35], which may affect various parameters at the cellular and molecular level [34,[40][41][42][43].…”

“…Potential limitations of these studies, as acknowledged by the investigators [21,22] is that JNK inhibitors may not be specific and as reported can affect other signaling events that could lead to the misinterpretation of results [36][37][38][39]. Further, some of the JNK inhibitors were dissolved in vehicles containing DMSO [14,21] and polyethylene glycol [22,35], which may affect various parameters at the cellular and molecular level [34,[40][41][42][43].In conclusion, our findings suggest that JNK2 plays a protective role against AILI in mice at least, in part, by modulating hepatocellular regeneration and repair. Although other research in mice provides evidence for JNK having a pathologic role in AILI, we feel that it is prudent to reconsider the use of JNK inhibitors as a therapeutic intervention in AILI [21,22,35,44].…”

Antioxidants as Biomarkers of Oxidative Stress

“…However, DMSO treatment did not affect the change of MAPKs by D -Galn (Iida et al 2007b ). However, DMSO treatment did not affect the change of MAPKs by D -Galn (Iida et al 2007b ).…”