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Protective effects of hepatocellular canalicular conjugate export pump (Mrp2) on sodium arsenite-induced hepatic
Guo-Xing Li1, Qiu-Ling Pei, Yi Gao
1Tianjin Centers for Disease Control and Prevention, Hedong District, Tianjin, PR China.
Abstract:
Arsenic is a double-edged sword to human health. The excretion of various organic anions into bile is mediated by an adenosine triphosphate-dependent conjugate export pump, which has been identified as the canalicular isoform of the multidrug resistance protein 2 (Mrp2). It has been proved that Mrp2 can transport arsenite in vitro, but its effects in vivo are not clear. The aim of this study was to investigate whether Mrp2 plays a role in exportation of arsenic in vivo and its protective effects on liver function. Mrp2 protein level in rat liver was determined by Western blot analysis. Total arsenic concentrations in whole blood and bile were measured using hydride generation atomic absorption spectrometry. Alanine aminotransferase (ALT) activity, aspartate aminotransferase activity (AST), glutathione peroxidase (GSH-PX) activity, malon dialdehyde (MDA) and total bilirubin were measured by biochemical assays. The morphological changes were observed by electron microscopy. Total arsenic levels in blood and bile of arsenite-treated rats were significantly higher than those of control rats (P<0.05) at all three different time points. The overexpression of Mrp2 was 36.61%, 32.36% and 12.73% at 2, 4 and 6 weeks, respectively (percentage of controls, P<0.05), which was significantly higher than controls. A positive correlation between Mrp2 expression level and total arsenic concentration in bile indicated that Mrp2 accelerated the transport of arsenic. Electron microscopy showed that microvilli of bile canaliculi became swollen and sparse. ALT and AST activities in serum were markedly raised at 6 weeks. MDA level in serum increased (P<0.05) and GSH-PX activity in serum decreased except for 2 weeks. Damage of liver function became worse following decreased expression of Mrp2. In conclusion, overexpression of Mrp2 may explain increased biliary excretion of arsenic and it may protect liver function.
Insights
Multidrug resistance-associated protein 2 (Mrp2) facilitates arsenic excretion in rats, protecting liver function. Increased Mrp2 expression correlates with higher arsenic levels in bile, suggesting a protective role against arsenic toxicity.
Area of Science:
- Toxicology
- Molecular Biology
- Hepatology
Background:
- Arsenic poses significant risks to human health.
- Biliary excretion of organic anions is mediated by the multidrug resistance-associated protein 2 (Mrp2).
- Mrp2's in vivo role in arsenic excretion and liver protection remains unclear.
Purpose of the Study:
- To investigate Mrp2's role in in vivo arsenic excretion.
- To determine Mrp2's protective effects on liver function following arsenic exposure.
Main Methods:
- Western blot analysis for Mrp2 protein levels in rat liver.
- Hydride generation atomic absorption spectrometry for total arsenic in blood and bile.
- Biochemical assays for liver function markers (ALT, AST, GSH-PX, MDA, bilirubin).
- Electron microscopy for bile canaliculi morphology.
Main Results:
- Arsenic exposure significantly increased total arsenic levels in blood and bile.
- Mrp2 protein expression was significantly overexpressed in arsenic-treated rats.
- A positive correlation was observed between Mrp2 expression and biliary arsenic concentration.
- Liver function markers indicated damage, worsening with decreased Mrp2 expression.
- Electron microscopy revealed bile canaliculi damage.
Conclusions:
- Overexpression of Mrp2 enhances biliary excretion of arsenic.
- Mrp2 plays a protective role in mitigating arsenic-induced liver damage.
- Targeting Mrp2 could be a strategy for managing arsenic toxicity.
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