马兜铃酸(AA)-IIIa是存在于马兜铃科植物中的AA类似物。为了评估AA-IIIa的慢性毒性,小鼠用培养基对照胃内给药,1mg/kgAA-IIIa,和10mg/kgAA-IIIa,并指定为对照(CTL),AA-IIIa低剂量(AA-Ⅲa-L),AA-IIIa高剂量组(AA-Ⅲa-H),分别。AA-IIIa每周给药三次,每隔一天,24周(24周时间点)。此后,一些老鼠被立即处死,而其他人则在AA-Ⅲa停药后29或50周(53或74周时间点)处死。收集血清和器官进行生化和病理分析,分别。对肾脏进行全基因组测序,肝脏,和AA-IIIa处理的小鼠的胃组织进行单核苷酸多态性(SNP)检测。AA-IIIa-H小鼠在66周时死亡,其余的小鼠在69周时表现出垂死的状况。AA-IIIa诱导的轻微肾小管损伤,成纤维细胞增生,和小鼠的前胃癌。膀胱,肠,肝脏,心,脾,脾肺,AA-IIIa对睾丸组织无病理改变。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,在24周时间点,AA-IIIa-H小鼠的肝脏和前胃组织中未观察到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有潜在的致突变作用.另一方面,前胃是老鼠特有的器官,但它不存在于人类中;因此,我们假设AA-Ⅲa引起的胃毒性不是人类毒理学评估的合适参考。我们建议对含有AA-IIIa的马兜铃科植物进行适当的监督,应避免过量服用和长期服用含有AA-IIIa的药物。
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, 1 mg/kg AA-IIIa, and 10 mg/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.