Gumpricht Eric, Dahl Rolf, Devereaux Michael W, Sokol Ronald J
Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado School of Medicine and The Children's Hospital, Denver, Colorado 80262, USA.
Pediatr Res. 2004 May;55(5):814-21. doi: 10.1203/01.PDR.0000117845.23762.6B. Epub 2004 Feb 5.
Hydrophobic bile acids are implicated in the pathogenesis of cholestatic liver disorders through mechanisms involving oxidative stress and mitochondrial dysfunction. Antioxidants ameliorate bile acid-induced cytotoxicity in rat hepatocyte suspensions. The purpose of the current study was to evaluate the potential protective role of beta-carotene (betaC), a putative fat-soluble antioxidant that is reduced in patients with cholestasis, against bile acid-induced hepatotoxicity. In freshly isolated rat hepatocyte suspensions that were exposed to the toxic hydrophobic bile acid glycochenodeoxycholic acid (100 or 500 microM), betaC (100 microM) decreased generation of reactive oxygen species by >50%, similar to the inhibition afforded by alpha-tocopherol. Commensurate with this antioxidant effect, 100 microM betaC also protected hepatocytes against both glycochenodeoxycholic acid-induced cellular necrosis and apoptosis, which was associated with reduction in caspase 3 activation, inhibition of mitochondrial cytochrome c release in rat hepatocytes, and prevention of the mitochondrial permeability transition in both liver mitochondria and rat hepatocytes. A lower concentration of betaC (50 microM) produced similar antioxidant and anti-apoptotic protection but with less inhibition against cell necrosis, suggesting that the higher concentration of betaC may have conferred additional cytoprotection not directly related to its antioxidant function. These results demonstrate that the antioxidant effects of betaC may provide hepatoprotection against cholestatic liver injury by preventing bile acid-induced oxidative stress and mitochondrial perturbations.
疏水性胆汁酸通过涉及氧化应激和线粒体功能障碍的机制参与胆汁淤积性肝病的发病过程。抗氧化剂可改善胆汁酸诱导的大鼠肝细胞悬液中的细胞毒性。本研究的目的是评估β-胡萝卜素（βC）的潜在保护作用，βC是一种假定的脂溶性抗氧化剂，在胆汁淤积患者中含量降低，可抵抗胆汁酸诱导的肝毒性。在新鲜分离的大鼠肝细胞悬液中，使其暴露于有毒的疏水性胆汁酸甘氨鹅去氧胆酸（100或500微摩尔），βC（100微摩尔）可使活性氧的生成减少>50%，这与α-生育酚所提供的抑制作用相似。与这种抗氧化作用相一致，100微摩尔的βC还可保护肝细胞免受甘氨鹅去氧胆酸诱导的细胞坏死和凋亡，这与半胱天冬酶3激活的减少、大鼠肝细胞线粒体细胞色素c释放的抑制以及肝线粒体和大鼠肝细胞中线粒体通透性转换的预防有关。较低浓度的βC（50微摩尔）产生了类似的抗氧化和抗凋亡保护作用，但对细胞坏死的抑制作用较小，这表明较高浓度的βC可能赋予了与其抗氧化功能不直接相关的额外细胞保护作用。这些结果表明，βC的抗氧化作用可能通过预防胆汁酸诱导的氧化应激和线粒体紊乱，为胆汁淤积性肝损伤提供肝脏保护。
