Adachi Makiko, Kumagai Takeshi, Hosho Keiko, Nagata Kiyoshi, Fujiyoshi Masachika, Shimada Miki
Department of Pharmacy, Tottori University Hospital, Yonago 683-8504, Japan.
Laboratory of Environmental and Health Sciences, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai 981-8558, Japan.
Yonago Acta Med. 2024 May 24;67(2):124-134. doi: 10.33160/yam.2024.05.004. eCollection 2024 May.
Patients taking multiple drugs and various health foods often develop acute hepatitis. We hypothesized that the interaction between health foods and drug metabolism was the cause of severe liver injury in these patients. Therefore, we studied changes in the activity of the drug-metabolizing enzyme, cytochrome P450 (CYP), using slimming health food extracts and elucidated the molecular mechanism of liver injury onset through hepatotoxicity evaluation.
For cytotoxicity testing, health food extract samples were added to HepG2 cells derived from hepatic parenchymal cells and culture medium, and cell viability was calculated 48 h after culture. To evaluate CYP3A4 induction, 3-1-10 cells constructed with a reporter linked to CYP3A4 gene were used, and reporter activity was measured 48 h after culture.
In the chronological order of the slimming health food intake history of the patient, niacinamide and extracts strongly inhibited HepG2 cell viability. In contrast, dietary supplements A and extract strongly induced CYP3A4 reporter activity.
To confirm CYP3A4 induction in humans, humanized CYP3A/pregnane X receptor (PXR) mice were treated with forskolin. CYP3A4 mRNA expression levels were elevated 3.9 times compared to that of the control group ( < 0.05).
extract showed the strongest transcriptional activation of CYP3A4 gene. In a mouse model of human-type drug metabolism, forskolin induced CYP3A4 transcription. Thus, we concluded that CYP3A4 induction by is one of the causes of crucial hepatocellular injury, which is a type of liver injury caused by the active metabolite of acetaminophen produced by CYP3A4.
服用多种药物和各类健康食品的患者常发生急性肝炎。我们推测健康食品与药物代谢之间的相互作用是这些患者发生严重肝损伤的原因。因此，我们使用减肥健康食品提取物研究了药物代谢酶细胞色素P450（CYP）活性的变化，并通过肝毒性评估阐明了肝损伤发病的分子机制。
对于细胞毒性测试，将健康食品提取物样品添加到源自肝实质细胞的HepG2细胞和培养基中，并在培养48小时后计算细胞活力。为了评估CYP3A4的诱导情况，使用构建有与CYP3A4基因相连的报告基因的3-1-10细胞，并在培养48小时后测量报告基因活性。
按照患者减肥健康食品摄入历史的时间顺序，烟酰胺及其提取物强烈抑制HepG2细胞活力。相比之下，膳食补充剂A及其提取物强烈诱导CYP3A4报告基因活性。
为了在人类中确认CYP3A4的诱导情况，用福司可林处理人源化CYP3A/孕烷X受体（PXR）小鼠。与对照组相比，CYP3A4 mRNA表达水平升高了3.9倍（P<0.05）。
提取物显示出对CYP3A4基因最强的转录激活作用。在人源化药物代谢小鼠模型中，福司可林诱导CYP3A4转录。因此，我们得出结论，提取物诱导CYP3A4是关键肝细胞损伤的原因之一，这种肝损伤是由CYP3A4产生的对乙酰氨基酚活性代谢物引起的一种肝损伤。
