Strain and interindividual differences in lamotrigine-induced liver injury in mice.
Strain and interindividual differences in lamotrigine-induced liver injury in mice.
复制标题
拉莫三嗪诱导的小鼠肝损伤的应变和个体间差异。
DOI：
10.1002/jat.3736
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发表时间：
2019
影响因子：
3.3
通讯作者：
and Tsuyoshi Yokoi.
中科院分区：
文献类型：
--
作者：
Sho Akai;Shingo Oda;and Tsuyoshi Yokoi.
拉莫三嗪（LTG）已被广泛用作抗精神病药物，尽管它会导致人类特异质药物诱导的肝损伤。LTG主要通过UDP-葡萄糖醛酸基转移酶代谢，而LTG通过细胞色素P450生物活化为反应性代谢物;随后与谷胱甘肽结合，表明反应性代谢物可能是LTG诱导的肝损伤的原因之一。然而，关于人类和啮齿类动物中LTG诱导的肝损伤机制的信息很少。在本研究中，我们通过联合给予LTG和谷胱甘肽合成抑制剂l-丁硫氨酸-（S，R）-亚砜亚胺建立了LTG诱导的肝损伤小鼠模型。我们发现C57 BL/6 J小鼠的丙氨酸氨基转移酶（ALT）水平升高（>10 000 U/L），具有明显的个体间差异。另一方面，在BALB/c小鼠中未观察到ALT急剧升高，表明两种菌株之间的启动机制不同。为了检查个体间差异的原因，基于ALT值将共同施用LTG和丁硫氨酸-（S，R）-亚砜亚胺的C57 BL/6 J小鼠分为三组：无应答者（ALT <100 U/L）、低应答者（100 U/L < ALT < 1000 U/L）和高应答者（ALT >1000 U/L）。在高应答组中，肝氧化应激、炎症和mRNA中损伤相关分子模式分子的诱导与肝细胞空泡化和核破裂相关。总之，我们证明LTG在肝损伤的启动和加重机制方面表现出明显的应变和个体差异。这些结果将支持对在人体中观察到的LTG诱导肝损伤机制的解释。
Lamotrigine (LTG) has been widely prescribed as an antipsychotic drug, although it causes idiosyncratic drug‐induced liver injury in humans. LTG is mainly metabolized by UDP‐glucuronosyltransferase, while LTG undergoes bioactivation by cytochrome P450 to a reactive metabolite; it is subsequently conjugated with glutathione, suggesting that reactive metabolite would be one of the causes for LTG‐induced liver injury. However, there is little information regarding the mechanism of LTG‐induced liver injury in both humans and rodents. In this study, we established an LTG‐induced liver injury mouse model through co‐administration with LTG and a glutathione synthesis inhibitor,l‐buthionine‐(S,R)‐sulfoximine. We found an increase in alanine aminotransferase (ALT) levels (>10 000 U/L) in C57BL/6J mice, with apparent interindividual differences. On the other hand, a drastic increase in ALT was not noted in BALB/c mice, suggesting that the initiation mechanism would be different between the two strains. To examine the cause of interindividual differences, C57BL/6J mice that were co‐administered LTG andl‐buthionine‐(S,R)‐sulfoximine were categorized into three groups based on ALT values: no‐responder (ALT <100 U/L), low‐responder (100 U/L < ALT < 1000 U/L) and high‐responder (ALT >1000 U/L). In the high‐responder group, induction of hepatic oxidative stress, inflammation and damage‐associated molecular pattern molecules in mRNA was associated with vacuolation and karyorrhexis in hepatocytes. In conclusion, we demonstrated that LTG showed apparent strain and interindividual differences in liver injuries from the aspects of initiation and exacerbation mechanisms. These results would support interpretation of the mechanism of LTG‐induced liver injury observed in humans.