Activation of mitogen activated protein kinase (MAPK) during carbon tetrachloride intoxication in the rat liver

Abstract

Carbon tetrachloride (CCl(4): 4 ml/kg body weight as a 1:1 mixture of CCl(4) and mineral oil) was orally administered to rats. After 12 h the activity of plasma AST (aspartate aminotransferase) and ALT (alanine aminotransferase) was significantly higher than that of the control group and plasma AST and ALT activities increased thereafter. These results indicated that the necrotic process was active at about 12 h and developed thereafter. After 2-24 h of CCl(4) administration, the hepatic level of vitamin C, the most sensitive indicator of oxidative stress, decreased significantly, indicating that oxidative stress was significantly enhanced as early as 2 h after CCl(4) intoxication and thereafter. Phosphorylated JNK (c-Jun NH(2)-terminal kinase) and phospho-ERK1/2 (extracellular signal-regulated kinase1/2) were significantly increased transiently 1-3 h after treatment with CCl(4), while phosphorylated p38 decreased significantly 1-24 h after CCl(4) treatment. These results indicated that the change in MAPKs (mitogen activated protein kinases) slightly preceded that in vitamin C, the most sensitive chemical indicator of oxidative stress.

Oxidative Stress in the Ischemic and Non-Ischemic Parts of the Rat Liver after Two-Thirds Ischemia/Reperfusion

“…ERK is particularly sensitive to oxidative stress and is activated by 100 mM hydrogen peroxide, i.e., as low a level as 100 mM of reactive oxygen species, in cultured rat hepatocytes, 36) so it may be difficult to detect a change of 100 mM in 2,000 mM of vitamin C in the liver, even if all hydrogen peroxide caused an equivalent decrease in vitamin C. The activation of ERK has preceded the decrease in liver ascorbate level with the oxidative stress caused by carbon tetrachloride and thioacetamide. 8,9) The vitamin C level in the present study was significantly decreased in the non-ischemic region, so the notion of ERK activation in this region is reasonable. This may be a cytoprotective reaction of the nonischemic lobes to the oxidative stress caused by I/R.…”

“…[23][24][25] The activation of MAPK is linked with cell death in the rat liver via oxidative stress. [7][8][9] The three major subclasses of the MAPK family are JNK, ERK1/2, and p38 MAPK. Phosphorylated JNK in the ischemic lobes was significantly higher 1.5 and 3 h after reperfusion when the oxidative stress was also significantly higher, as was evident by the liver vitamin C level (Table 1), and liver necrosis was active based on the plasma AST and ALT levels ( Table 1).…”

“…Tel/Fax: +81-742-20-3459; E-mail: kojo@cc.nara-wu.ac.jp Abbreviations: ALT, alanine aminotransferase (EC 2.6.1.2); AST, aspartate aminotransferase (EC 2.6.1.1); ERK, extracellular signal-related kinase; I/R, ischemia/reperfusion; JNK, c-Jun NH 2 -terminal kinase; MAPK, mitogen-activated protein kinase; TNF-, tumor necrosis factor-Analytical methods. Vitamin C was determined by a specific and sensitive method [4][5][6][7][8][9][10] involving chemical conversion and HPLC. The concentration of -tocopherol was determined by HPLC.…”

“…[1][2][3] Although strenuous efforts have been made to finding a biomarker for oxidative stress, no reliable biomarker that quantitatively reflects tissue oxidative stress has yet been established. We have demonstrated in a series of studies [4][5][6][7][8][9] that the liver concentration of vitamin C and the activation of MAPKs (mitogen-activated protein kinases) were both very sensitive indices of oxidative stress by using experimental hepatitis caused by chemicals as the model system. We apply these results in the present study to evaluate the oxidative stress due to I/R injury, especially focusing on the oxidative stress in the non-ischemic lobules as a direct effect of liver I/R.…”

The Role of Kupffer Cells in Carbon Tetrachloride Intoxication in Mice

“…1) Many studies have demonstrated that lipid peroxidation of liver cell endoplasmic reticulum initiated by the trichloromethyl radical generated by the reaction between CCl 4 and cytochrome P450 is the initial event that occurs as early as 2 h after CCl 4 intoxication in rats. 1,2) Thereafter, the resulting severe oxidative stress persisted for at least 36 h 3) despite the concentration of CCl 4 in the liver having decreased rapidly from the maximal level attained at 1.5 h. 4) CCl 4 causes many intracellular events including activation of mitogen activated protein kinase (MAPK), 5,6) sphingomyelinase, 3) nuclear factor-κB (NF-κB), 7) and cyclooxygenase-2 (COX-2). 8) Humoral factors may be involved in these inflammatory events and, therefore, CCl 4 -induced hepatic injury is assumed to involve two phases.…”