Altered arsenic disposition in experimental nonalcoholic fatty liver disease.
Nonalcoholic fatty liver disease (NAFLD) is represented by a spectrum of liver pathologies ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). Liver damage sustained in the progressive stages of NAFLD may alter the ability of the liver to properly metabolize and eliminate xenobiotics. The purpose of the current study was to determine whether NAFLD alters the disposition of the environmental toxicant arsenic. C57BL/6 mice were fed either a high-fat or a methionine-choline-deficient diet to model simple steatosis and NASH, respectively. At the conclusion of the dietary regimen, all mice were given a single oral dose of either sodium arsenate or arsenic trioxide. Mice with NASH excreted significantly higher levels of total arsenic in urine (24 h) compared with controls. Total arsenic in the liver and kidneys of NASH mice was not altered; however, NASH liver retained significantly higher levels of the monomethyl arsenic metabolite, whereas dimethyl arsenic was retained significantly less in the kidneys of NASH mice. NASH mice had significantly higher levels of the more toxic trivalent form in their urine, whereas the pentavalent form was preferentially retained in the liver of NASH mice. Moreover, hepatic protein expression of the arsenic biotransformation enzyme arsenic (3+ oxidation state) methyltransferase was not altered in NASH animals, whereas protein expression of the membrane transporter multidrug resistance-associated protein 1 was increased, implicating cellular transport rather than biotransformation as a possible mechanism. These results suggest that NASH alters the disposition of arsenical species, which may have significant implications on the overall toxicity associated with arsenic in NASH.
Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, USA.
Mark J
MJ
Canet
Rhiannon N
RN
Hardwick
April D
AD
Lake
Michael J
MJ
Kopplin
George L
GL
Scheffer
Walter T
WT
Klimecki
A Jay
AJ
Gandolfi
Nathan J
NJ
Cherrington
D000818:Animals; D001149:Arsenates / Q000493:pharmacokinetics* / Q000633:toxicity / Q000652:urine; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000493:pharmacokinetics* / Q000652:urine; D001711:Biotransformation; D002796:Choline Deficiency / Q000150:complications; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004785:Environmental Pollutants / Q000493:pharmacokinetics* / Q000633:toxicity / Q000652:urine; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism* / Q000652:urine; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008715:Methionine / Q000172:deficiency; D008780:Methyltransferases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease; D010087:Oxides / Q000493:pharmacokinetics* / Q000633:toxicity / Q000652:urine
D001149:Arsenates; D000077237:Arsenic Trioxide; D001152:Arsenicals; D004785:Environmental Pollutants; D008715:Methionine; D008780:Methyltransferases; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010087:Oxides; C009277:sodium arsenate; C532135:AS3MT protein, mouse; C421109:multidrug resistance-associated protein 1