Abstract
The aim of this study was to determine whether calcium potentiates acute carbon tetrachloride (CCl4) -induced toxicity. Elevated calcium levels were induced in mice by pre-treatment with cholecalciferol (vitamin D3; V.D3), a compound that has previously been shown to induce hypercalcemia in human and animal models. As seen previously, mice injected with CCl4 exhibited increased plasma levels of alanine aminotransferase, aspartate aminotransferase, and creatinine; transient body weight loss; and increased lipid peroxidation along with decreased total antioxidant power, glutathione, ATP, and NADPH. Pre-treatment of these animals with V.D3 caused further elevation of the values of these liver functional markers without altering kidney functional markers; continued weight loss; a lower lethal threshold dose of CCl4; and enhanced effects on lipid peroxidation and total antioxidant power. In contrast, exposure to V.D3 alone had no effect on plasma markers of liver or kidney damage or on total antioxidant power or lipid peroxidation. The potentiating effect of V.D3 was positively correlated with elevation of hepatic calcium levels. Furthermore, direct injection of CaCl2 also enhanced CCl4-induced hepatic injury. Since CaCl2 induced hypercalcemia transiently (within 3 h of injection), our results suggest that calcium enhances the CCl4-induced hepatotoxicity at an early stage via potentiation of oxidative stress.
Highlights
Carbon tetrachloride (CCl4) is widely used in experimental animal models of liver failure that mimic human hepatic toxicity
Four-time, once-daily pre-treatment with V.D3 significantly increased plasma Ca concentrations to 13.0 mg/dL compared to the control value of 7.7 mg/dL (Table 2); these elevated levels would be classified as severe hypercalcemia
In parallel with the measurement of alanine aminotransferase (ALT) and aspartate amino transferase (AST), we evaluated plasma creatinine and blood urea nitrogen (BUN) levels, which are markers of renal injury
Summary
Carbon tetrachloride (CCl4) is widely used in experimental animal models of liver failure that mimic human hepatic toxicity. CCl4-induced toxicity is a multifactorial process involving the generation of CCl4-derived free radicals [2,3,4,5]. The first step is metabolic activation of CCl4 by CYP2E1, whereby CCl4 is converted to free. The second step is binding of these radicals to antioxidant enzymes, including the sulfhydryl (protein thiol) groups of glutathione (GSH). These overproduced free radicals increase membrane lipid peroxidation, bind covalently to macromolecules, deplete ATP, and interfere with calcium homeostasis [6,7,8]. Since sulfhydryl groups are essential elements of the molecular arrangements responsible for the Ca2+ transport across cellular membranes, loss of function of these proteins is expected to impair the capacity of microsomes and mitochondria to regulate cellular calcium levels
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