No abstract

The different methyl metabolic products of inorganic arsenic lead to various toxicities. Arsenic has been demonstrated to induce hepatotoxicity by oxidative stress. The relationship between hepatic injury and inorganic methylation is not yet known. This study was designed to explore the relationship between arsenic methylation and liver oxidative stress induced by arsenic trioxide (ATO). Forty healthy KM mice were randomly divided into control group (0.9% saline) and As 2 O 3 (1.0 mg/Kg/day, 2.0 mg/Kg/day, 4.0 mg/Kg/day) groups with gastric perfusion for five weeks using high-efficiency liquid chromatography and hydride genesis atomic fluorescence spectroscopy (HPLC-HGAFS). The products of arsenic trioxiode methylating, including trivalent inorganic arsenic (iAs 3+ ), pentavalent inorganic arsenic (iAs 5+ ), mono methyl arsenic (MMA), and dimethyl arsenic (DMA) in the liver were determined. The indexes of arsenic methylation, including primary methyl index (PMI) and second methyl index (SMI) were calculated. The level of hepatic function and activity of MDA, GSH, SOD, and TAOC were detected with kits. We found that the remaining arsenic metabolic products in liver significantly increased with the increasing doses of arsenic trioxide and the liver function and oxidative stress deteriorated. Negative correlations were found between MMA%, PMI and GSH, SOD, and TAOC, while DMA% and SMI positively correlated with the levels of ALT and AST. PMI and SMI negatively correlated with TAOC, GSH, SOD, ALT, and AST, positively linked with the level of MDA. The present study demonstrates that the hepatotoxicity induced by the arsenic accounts for deteriorating oxidative injury activized by arsenic methylation metabolism, providing additional evidence to suggest a mechanism of arsenic poisoning. Therefore, reducing the process of arsenic methylation may be potentially benefical in treating and -more importantly -preventing arseniasis.

This study investigated the effects of proanthocyanidins (PC) on arsenic methylation metabolism and efflux in human hepatocytes (L-02), as well as the relationships between PC and GSH, MRP1 and other molecules. Cells were randomly divided into blank control group, arsenic trioxide exposure group (ATO, As2O3, 25μmol/L), and PC-treated arsenic exposure group (10, 25, 50mg/L). After 24/48h, the contents of different forms of arsenic were determined, and the methylation indexes were calculated. Intracellular S-adenosyl methionine (SAM), arsenic (+3 oxidation state) methyltransferase (AS3MT), multidrug resistance-associated protein 1 (MRP1), and reduced glutathione (GSH) were ascertained. Changing trends were observed and the correlation between arsenic metabolism and efflux related factors and arsenic metabolites was analyzed. We observed that cells showed increased levels of content/constituent ratio of methyl arsenic, primary/secondary methylation index, methylation growth efficiency/rate, and the difference of methyl arsenic content in cells and culture medium (P<0.05, resp.). Compared with ATO exposure group, the intracellular SAM content in PC-treated group decreased, and the contents of GSH, AS3MT, and MRP1 increased (P<0.05, resp.). There was a positive correlation between the content of intracellular GSH/AS3MT and methyl arsenic. The content of MRP1 was positively correlated with the difference of methyl arsenic content in cell and culture medium; conversely, the SAM content was negatively correlated with intracellular methyl arsenic content (P<0.05, resp.). Taken together, these results prove that PC can promote arsenic methylation metabolism and efflux in L-02 cells, which may be related to the upregulation of GSH, MRP1, and AS3MT levels by PC.