Sciadvisor Toxicology Consulting, P.O. Box 254, Hadlyme, CT 06439, USA.
Toxicology. 2011 Jan 11;279(1-3):10-8. doi: 10.1016/j.tox.2010.10.006. Epub 2010 Oct 23.
Hepatic steatosis is characterized by the accumulation of lipid droplets in the liver. Although relatively benign, simple steatosis can eventually lead to the development of steatohepatitis, a more serious condition characterized by fibrosis, cirrhosis, and eventual liver failure if the underlying cause is not eliminated. According to the "two hit" theory of steatohepatitis, the initial hit involves fat accumulation in the liver, and a second hit leads to inflammation and subsequent tissue injury. Because some xenobiotics target liver fatty acid metabolism, especially mitochondrial β-oxidation, it is important to avoid potential drug candidates that can contribute to either the initiation of liver steatosis or progression to the more injurious steatohepatitis. The gold standard for the detection of these types of hepatic effects is histopathological examination of liver tissue. In animal studies, these examinations are slow, restricted to a single sampling time, and limited tissue sections. Recent literature suggests that rapid in vitro screening methods can be used early in the drug R&D process to identify compounds with steatotic potential. Further, progress in the identification of potential serum or plasma protein biomarkers for these liver changes may provide additional in vivo tools to the preclinical study toxicologist. This review summarizes recent developments for in vitro screening and in vivo biomarker detection for steatotic drug candidates.
肝脂肪变性的特征是肝脏中脂滴的积累。虽然相对良性，但单纯性脂肪变性最终可导致更严重的肝脂肪肝炎的发生，其特征为纤维化、肝硬化，如果不消除潜在病因，最终可能导致肝衰竭。根据肝脂肪肝炎的“双打击”理论，最初的打击涉及肝脏脂肪堆积，第二次打击导致炎症和随后的组织损伤。由于一些外来物质针对肝脏脂肪酸代谢，特别是线粒体β-氧化，因此避免可能导致肝脂肪变性起始或进展为更具损伤性的肝脂肪肝炎的潜在药物候选物非常重要。这些类型肝作用的金标准检测方法是肝组织的组织病理学检查。在动物研究中，这些检查速度较慢，限于单一采样时间，且受限于组织切片。最近的文献表明，快速的体外筛选方法可在药物研发过程的早期用于识别具有脂肪变性潜力的化合物。此外，鉴定这些肝变化潜在血清或血浆蛋白生物标志物的进展可能为临床前研究毒理学家提供额外的体内工具。本文综述了用于筛选脂肪变性药物候选物的体外和体内生物标志物检测的最新进展。
