马兜铃酸 (AA)-IIIa 是马兜铃科植物中存在的 AA 类似物。为了评价AA-IIIa的慢性毒性，给小鼠灌胃培养基对照，1mg/kg AA-IIIa和10mg/kg AA-IIIa，并指定为对照(CTL)，AA-IIIa低剂量(AA-分别为Ⅲa-L)组和AA-IIIa高剂量组(AA-Ⅲa-H)组。 AA-IIIa 每周施用 3 次，每隔一天施用一次，持续 24 周（24 周时间点）。此后，一些小鼠立即处死，而另一些小鼠在AA-Ⅲa停药后29或50周（53或74周时间点）处死。收集血清和器官分别用于生化和病理分析。对 AA-IIIa 治疗小鼠的肾脏、肝脏和胃组织进行全基因组测序，以检测单核苷酸多态性 (SNP)。 AA-IIIa-H小鼠在66周时死亡，其余小鼠在69周时表现出垂死状态。 AA-IIIa 可诱导小鼠轻微肾小管损伤、成纤维细胞增生和前胃癌。 AA-IIIa 未对膀胱、肠、肝脏、心脏、脾脏、肺和睾丸组织造成病理改变。此外，AA-IIIa 增加了肾脏中的 C:G > A:T 突变；然而，与对照小鼠相比，24周时间点AA-IIIa-H小鼠的肝脏和前胃组织中没有观察到SNP突变变化。因此，我们怀疑AA-IIIa在过量和长期给药后对小鼠具有潜在的致突变性。另一方面，前胃是小鼠特有的器官，但在人类中并不存在；因此，我们推测AA-Ⅲa引起的胃毒性不适合作为人体毒理学评价的参考。我们建议对含有 AA-IIIa 的马兜铃科植物进行适当监管，避免过量和长期服用含有 AA-IIIa 的药物。版权所有 © 2024 Elsevier B.V. 保留所有权利。

Aristolochic acid (AA)-IIIa is an AA analog present in Aristolochiaceae plants. To evaluate the chronic toxicity of AA-IIIa, mice were intragastrically administered with media control, 1mg/kg AA-IIIa, and 10mg/kg AA-IIIa, and designated as the control (CTL), AA-IIIa low dose (AA-Ⅲa-L), and AA-IIIa high dose (AA-Ⅲa-H) groups, respectively. AA-IIIa was administered three times a week, every other day, for 24 weeks (24-week time point). Thereafter, some mice were sacrificed immediately, while others were sacrificed 29 or 50 weeks after AA-Ⅲa withdrawal (53- or 74-week time point). Serum and organs were collected for biochemical and pathological analyses, respectively. Whole-genome sequencing was performed on the kidney, liver, and stomach tissues of AA-IIIa-treated mice for single-nucleotide polymorphism (SNP) detection. AA-IIIa-H mice died at 66 weeks, and the remaining mice showed moribund conditions at the 69 weeks. AA-IIIa induced minor kidney tubule injury, fibroblast hyperplasia, and forestomach carcinoma in mice. Bladder, intestine, liver, heart, spleen, lung, and testis tissues were not pathologically altered by AA-IIIa. In addition, AA-IIIa increased the C:G > A:T mutation in the kidney; however, no SNP mutation changes were observed in the liver and forestomach tissues of AA-IIIa-H mice at the 24-week time point compared with control mice. Therefore, we suspect that AA-IIIa is potentially mutagenic for mice after overdose and long-term administration. On the other hand, the forestomach is a unique organ in mice, but it does not exist in humans; thus, we hypothesize that the stomach toxicity induced by AA-Ⅲa is not a suitable reference for toxicological evaluation in humans. We recommend that Aristolochiaceae plants containing AA-IIIa should be properly supervised, and overdosing and long-term administration of drugs containing AA-IIIa should be avoided.Copyright © 2024 Elsevier B.V. All rights reserved.