Reagan William J, Yang Rong-Ze, Park Soohyun, Goldstein Richard, Brees Dominique, Gong Da-Wei
Drug Safety Research and Development, Pfizer Worldwide Research and Development, Eastern Point Rd., MS 274/1203, Groton, CT 06340, USA.
Toxicol Pathol. 2012 Dec;40(8):1117-27. doi: 10.1177/0192623312447550. Epub 2012 May 18.
Alanine aminotransferase (ALT) is used as an indicator of hepatocellular injury. Since ALT consists of two isoenzymes, a better understanding of ALT isoenzyme biology in response to compounds that cause metabolic adaptive versus hepatotoxic responses will allow for a more accurate assessment of the significance of an ALT increase. The purpose of this study was to characterize the ALT isoenzyme response in mice treated with 25 or 75 mg/kg of dexamethasone, which is known to induce a progluconeogenic state, for 24 or 72 hr. Those mice treated with 75 mg/kg for 72 hr showed an increase in total liver ALT activity. Western blot showed that there was an increase in ALT2 at both doses and time points and there was a concurrent increase in ALT2 ribonucleic acid at 24 and 72 hr. The ALT isoenzyme response assessed by an activity assay showed an increase in ALT2. The increases in liver ALT were associated with an increase in liver glycogen and there was no hepatocellular necrosis. There was an increase in total serum ALT activity, although serum isoenzymes were not evaluated. Thus, the authors demonstrated that dexamethasone induced increases in hepatic and serum ALT, which reflect a hepatocellular progluconeogenic metabolic adaptive response.
丙氨酸转氨酶（ALT）用作肝细胞损伤的指标。由于ALT由两种同工酶组成，更好地了解ALT同工酶对引起代谢适应性与肝毒性反应的化合物的生物学反应，将有助于更准确地评估ALT升高的意义。本研究的目的是表征用25或75mg/kg地塞米松处理24或72小时的小鼠的ALT同工酶反应，已知地塞米松可诱导糖异生状态。那些用75mg/kg处理72小时的小鼠肝脏ALT总活性增加。蛋白质印迹显示，在两个剂量和时间点ALT2均增加，并且在24和72小时时ALT2核糖核酸同时增加。通过活性测定评估的ALT同工酶反应显示ALT2增加。肝脏ALT的增加与肝糖原增加相关，且无肝细胞坏死。血清ALT总活性增加，尽管未评估血清同工酶。因此，作者证明地塞米松诱导肝脏和血清ALT增加，这反映了肝细胞糖异生代谢适应性反应。
