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Toxicokinetic and genomic analysis of chronic arsenic exposure in multidrug-resistance mdr1a-1b(-/-) double knockout mice

Curtis D.Klaassen;Michael.Waalkes

  Multidrug-resistance gene knockout mdr1a/1b(-/-) mice,which are deficient in P-glycoproteins,are more sensitive than wild-type(WT) mice to acute arsenic toxicity.This study assessed toxic manifestations of chronic oral arsenic in mkr1a/1b(-/-) mice including oxidative stress and altered gene expression,and investigated altered toxicokinetics as a potential basis of enhanced arsenic toxicity.Thus, mdr1a/1b(-/-) and WT mice were exposed to sodium arsenite(0-80 ppm as arsenic) in the drinking water for 10 weeks at which time hepatic arsenic accumulation,lipid peroxidation(LPO),redox status and change in gene expression level were assessed.All mice survived the arsenic exposure,but body weight gain in the highest dose group was reduced in both mdr1a/1b(-/-) than in WT mice.Arsenic induced pathological changes, elevated LPO levels and enhanced glutathione S-transferase(GST) activity,in the liver to a greater extent in mdr1a/1b(-/-) than in WT mice.Arsenic also decreased Cu-Zn superoxide dismutase activity in both mdr1a/1b(-/-) and WT mice.The expressions of certain genes,such as those encoding cell proliferation,GST, acute-phase proteins and metabolic enzymes,were modestly altered in arsenic-exposed mice.The expression of cyclin D1,a potential hepatic oncogenen,was enhanced in arsenic-exposed mdr1a/1b(-/-) mice only.At the highest level of exposure,hepatic arsenic content was higher in mdr1a/1b(-/-) than in WT mice,suggesting that enhanced accumulation due to transport deficient may,in part,account for the enhanced toxicity in these mice,In summary,this study shows that chronic arsenic toxicity,including liver pathology and oxidative stress, is enhanced in mdr1a/1b(-/-) mice,possibly due to enhanced accumulation of arsenic as a result of transport system deficiency.……