Pritt Michael L, Hall David Greg, Recknor Justin, Credille Kelly M, Brown Donna D, Yumibe Nathan P, Schultze Albert Eric, Watson David E
Investigative Toxicology, Lilly Research Laboratories, Greenfield, Indiana 46140, USA.
Toxicol Sci. 2008 Jun;103(2):382-96. doi: 10.1093/toxsci/kfn042. Epub 2008 Feb 27.
Fatty acid binding protein 3 (Fabp3) has been used as a serological biomarker of cardiac injury, but its utility as a preclinical biomarker of injury to skeletal muscle is not well described. Fabp3 concentrations were determined for tissues from Sprague-Dawley rats and found to occur at highest concentrations in cardiac muscle and in skeletal muscles containing an abundance of type I fibers, such as the soleus muscle. Soleus is also a primary site of skeletal muscle (SKM) injury caused by lipid-lowering peroxisome proliferator-activated receptor alpha (PPAR-alpha) agonists. In rats administered repeat doses of a PPAR-alpha agonist, the kinetics and amplitude of plasma concentrations of Fabp3 were consistent with plasma compound concentrations and histopathology findings of swollen, hyalinized, and fragmented muscle fibers with macrophage infiltration. Immunohistochemical detection of Fabp3 revealed focal depletion of Fabp3 protein from injured SKM fibers which is consistent with increased serum Fabp3 concentrations in treated rats. We then assessed the predictivity of serological Fabp3 for SKM necrosis in short duration toxicology studies. Rats were treated with various doses of 27 different compounds, and the predictivity of serological biomarkers was assessed relative to histology in individual rats and in treatment groups. Under these study conditions, Fabp3 was the most useful individual biomarker based on concordance, sensitivity, positive and negative predictive values, and false negative rate. In addition, the combination of Fabp3 and aspartate aminotransferase (AST) had greater diagnostic value than the conventional combination of creatine kinase-MM isoenzyme (CK) and AST.
脂肪酸结合蛋白3（Fabp3）已被用作心脏损伤的血清生物标志物，但其作为骨骼肌损伤临床前生物标志物的效用尚未得到充分描述。测定了来自Sprague-Dawley大鼠组织中的Fabp3浓度，发现其在心肌和含有大量I型纤维的骨骼肌（如比目鱼肌）中浓度最高。比目鱼肌也是降脂过氧化物酶体增殖物激活受体α（PPAR-α）激动剂引起的骨骼肌（SKM）损伤的主要部位。在重复给予PPAR-α激动剂的大鼠中，Fabp3血浆浓度的动力学和幅度与血浆化合物浓度以及肌肉纤维肿胀、透明变性和断裂并伴有巨噬细胞浸润的组织病理学结果一致。Fabp3的免疫组织化学检测显示，受损SKM纤维中Fabp3蛋白局部缺失，这与治疗大鼠血清Fabp3浓度升高一致。然后，我们在短期毒理学研究中评估了血清Fabp3对SKM坏死的预测性。用27种不同化合物的各种剂量处理大鼠，并相对于个体大鼠和治疗组中的组织学评估血清生物标志物的预测性。在这些研究条件下，基于一致性、敏感性、阳性和阴性预测值以及假阴性率，Fabp3是最有用的个体生物标志物。此外，Fabp3和天冬氨酸转氨酶（AST）的组合比肌酸激酶-MM同工酶（CK）和AST的传统组合具有更大的诊断价值。
