Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, 466-8550, Japan.
J Appl Toxicol. 2019 Mar;39(3):451-460. doi: 10.1002/jat.3736. Epub 2018 Oct 16.
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 and l-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.
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发性药物性肝损伤。LTG 主要通过 UDP-葡萄糖醛酸基转移酶代谢，而 LTG 则通过细胞色素 P450 生物转化为活性代谢物；随后与谷胱甘肽结合，表明活性代谢物可能是 LTG 诱导肝损伤的原因之一。然而，关于 LTG 在人类和啮齿动物中引起肝损伤的机制知之甚少。在这项研究中，我们通过联合使用 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 C57BL/6J 小鼠的丙氨酸氨基转移酶（ALT）水平升高（>10000 U/L），且个体间差异明显。另一方面，BALB/c 小鼠中未观察到 ALT 的急剧升高，这表明两种品系的起始机制可能不同。为了研究个体间差异的原因，根据 ALT 值将接受 LTG 和 L-丁硫氨酸（S，R）-亚砜亚胺联合给药的 C57BL/6J 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）。在高应答者组中，肝氧化应激、炎症和损伤相关分子模式分子的诱导与肝细胞空泡化和核碎裂有关。总之，我们从起始和加重机制方面证明了 LTG 在肝损伤方面表现出明显的品系和个体间差异。这些结果将支持对人类观察到的 LTG 诱导肝损伤机制的解释。
