Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, USA.
Drug Metab Dispos. 2012 Sep;40(9):1817-24. doi: 10.1124/dmd.112.046177. Epub 2012 Jun 14.
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.
非酒精性脂肪性肝病（NAFLD）表现为一系列肝脏病变，从单纯性脂肪变性到非酒精性脂肪性肝炎（NASH）不等。NAFLD 进展阶段持续的肝损伤可能改变肝脏正确代谢和消除外源性化学物质的能力。本研究旨在确定 NAFLD 是否改变环境毒物砷的处置方式。C57BL/6 小鼠分别用高脂肪或蛋氨酸-胆碱缺乏饮食喂养，以分别建立单纯性脂肪变性和 NASH 模型。在饮食方案结束时，所有小鼠均单次口服亚砷酸钠或三氧化二砷。与对照组相比，NASH 小鼠尿液（24 小时）中总砷排泄量显著增加。NASH 小鼠肝和肾中的总砷含量没有改变；然而，NASH 肝中保留了显著更高水平的单甲基砷代谢物，而 NASH 肾中保留的二甲基砷则显著减少。NASH 小鼠尿液中具有更高毒性的三价砷形式水平显著升高，而五价砷则优先保留在 NASH 小鼠的肝中。此外，NASH 动物肝中砷（+3 氧化态）甲基转移酶的砷生物转化酶的蛋白表达没有改变，而膜转运蛋白多药耐药相关蛋白 1 的蛋白表达增加，暗示细胞转运而不是生物转化可能是一种可能的机制。这些结果表明，NASH 改变了砷类物质的处置方式，这可能对与 NASH 相关的砷的整体毒性产生重大影响。
