Induction of hepatotoxicity by sanguinarine is associated with oxidation of protein thiols and disturbance of mitochondrial respiration

Abstract

Sanguinarine (SANG) has been suggested to be one of the principle constituents responsible for the toxicity of Argemone mexicana seed oil. In this study, we focused on the possible mechanism of SANG-induced hepatotoxicity. The serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) activities, hepatic vacuolization, lipid accumulation and lipid peroxidation of the liver were increased, and triglyceride (TG) was decreased in SANG-treated mice (10 mg kg(-1) i.p.), indicating damage to the liver. SANG induced cell death and DNA fragmentation, in a concentration- (0-30 microm) and time-dependent (0-24 h) manner, and the cytotoxicity of SANG (15 microm) was accompanied by an increase in reactive oxygen species and a lessening in protein thiol content; these outcomes were reversed by glutathione, N-acetyl-l-cysteine and 1,4-dithiothretol, and slightly improved by other antioxidants in hepatocytes. SANG can affect the function of mitochondria, leading to the depletion of the mitochondrial membrane potential and adenosine 5'-triphosphate content of hepatocytes. SANG caused an uncoupling effect of the respiratory chain at lower concentrations, but inhibited the respiratory chain at higher concentrations in mitochondria isolated from rat liver. In conclusion, the data suggest that SANG is a liver toxin that induces cytotoxicity in liver cells, possibly through oxidation of protein thiols, resulting in oxidative stress on the cells and disturbance of mitochondrial function.

Antitumor effects of the benzophenanthridine alkaloid sanguinarine: Evidence and perspectives

“…In that study, and in agreement with our findings, the anti-proliferative and anti-angiogenic effects of the oral sanguinarine administration were observed at a dosage, i.e., 5 mg/kg, devoid of apparent toxicity. On the other hand, an increase of serum levels of transaminases and LDH, hepatic vacuolization, lipid accumulation and peroxidation in the liver and a reduction of triglycerides, were observed in mice treated with high-dose sanguinarine (10 mg/kg), suggesting liver injury [94] . Previous studies showed that sanguinarine can cause physiological dysfunction in skeletal, smooth and cardiac muscles [95][96][97] .…”

Chelidonium majus is not hepatotoxic in Wistar rats, in a 4 weeks feeding experiment

“…Notable is that in various preclinical studies the major toxicity is generally attributed to its alkaloids. In particular, sanguinarine and chelerithrine are the most studied and are considered the most biologically effective as well as hepatotoxic chemical components (Williams et al, 2000;Choy et al, 2008). Indeed, sanguinarine (5-10 mg/kg) after intraperitoneal administration has been shown to induce liver damage in mice, and to significantly decrease hepatic glutathione and P450 enzymes activities (Williams et al, 2000;Choy et al, 2008).…”

“…Indeed, sanguinarine (5-10 mg/kg) after intraperitoneal administration has been shown to induce liver damage in mice, and to significantly decrease hepatic glutathione and P450 enzymes activities (Williams et al, 2000;Choy et al, 2008). In liver cell cultures, the alkaloid resulted cytotoxic by inducing oxidative stress and disturbance of mitochondrial function (Choy et al, 2008). On the other hand, 90-days oral administration of sanguinarine and chelerythrine from Macleya cordata, at 5 mg/kg alkaloids, proved to be safe in pigs: treated animals did not display any hematological, biochemical or histological alteration in comparison to controls (Kosina et al, 2004).…”

“…In particular, sanguinarine and chelerithrine are the most studied and are considered the most biologically effective as well as hepatotoxic chemical components (Williams et al, 2000;Choy et al, 2008). Indeed, sanguinarine (5-10 mg/kg) after intraperitoneal administration has been shown to induce liver damage in mice, and to significantly decrease hepatic glutathione and P450 enzymes activities (Williams et al, 2000;Choy et al, 2008). In liver cell cultures, the alkaloid resulted cytotoxic by inducing oxidative stress and disturbance of mitochondrial function (Choy et al, 2008).…”

Drug-induced liver injury due to “natural products” used for weight loss: A case report

“…The hepatic damage caused by these agents, generally of a cholestatic type, is possibly mediated by an idiosyncratic or hypersensitivity reaction. Recently, a different hypothesis was proposed involving an impairment of mitochondrial respiration [8] .…”