临床前药物安全性评价中关于肝细胞肥大的探讨

Discussion on hepatocyte hypertrophy in preclinical drug safety evaluation

临床前药物安全性评价研究中常常发现药物可诱导实验动物的肝细胞肥大,可能并伴有肝脏质量增加或血清生化中肝损伤指标的变化。近年来研究表明,众多化合物可以通过激活核内激素受体组成型雄甾烷受体(CAR)或过氧化物酶体激活受体α(PPARα)的机制诱导肝细胞肥大,并且该作用机制具有啮齿类动物的种属特异性,与人类缺乏相关性。然而,如何判定肝细胞肥大是不良反应还是非不良反应(适应性反应)是病理学家与毒理学家面临的挑战。该文从肝细胞肥大的定义、肝脏质量、临床病理学变化以及组织病理学变化等全面阐述了肝细胞肥大的特点,并依据证据权重分析方法探讨评估肝细胞肥大的预测风险。

Preclinical drug safety evaluation studies have often found that drugs can induce hepatocyte hypertrophy in experimental animals, which may be accompanied by increased lver weight or changes of the indicators of liver injury in serum. Recent studies have shown that hepatocyte hypertrophy may be induced by many xenobiotics through a common mechanism of activation of the nuclear receptors CAR (constitutive androstane receptor) or PPARα (peroxisome activated receptor alpha), and the machanism is rodent-specific and is not related to humans. However, it is a common challenge for pathologists and toxicologists to clearly define what is considered adverse or non-adverse (adaptive response) in the context of hepatocellular hypertrophy. In this paper, the characteristics of hepatocellular hypertrophy were discussed from the definition, liver weights, clinical pathology and histopathology changes, and the predictive risk of hepatocellular hypertrophy was evaluated by weight of evidence analysis.