Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
Biomed Pharmacother. 2021 Oct;142:112081. doi: 10.1016/j.biopha.2021.112081. Epub 2021 Aug 25.
Previous reports demonstrated that aristolochic acids (AAs) exposure-induced nephrotoxicity, mutations, and tumorigenesis are mainly due to aristolochic acid I (AAI). Notably, the chemical structure of aristolochic acid IVa (AAIVa), which exists at higher levels in many Aristolochiaceae herbs, is extremely similar to AAI. In lack of toxicological data, it is unknown whether AAIVa exposure leads to aristolochic acid nephropathy (AAN), mutations, and tumorigenesis as of AAI. To answer these questions, mice were administered AAIVa by single or repeated long-term gavage, while AAI was used as a positive control. We found that single gavage of 40 mg/kg of AAIVa exhibited no obvious toxicity. Also, there were no tumors or death in mice administrated with 1 and 10 mg/kg of AAIVa for 6 months followed by a 12-month recovery time. There were no noteworthy alterations in gene mutation frequency in the kidney, liver, and stomach between the AAIVa and control mice. Fascinatingly, AA-associated mutational signatures, adenine-to-thymine (A>T) transversions, were absent in AAIVa-treated mice. Nonetheless, 10 mg/kg of AAIVa triggered lymphocytic infiltration and slight fibrous hyperplasia in the kidney at the 6 month; however, these were alleviated at the 12 and 18 months. On the contrary, AAI (positive control) caused severe diffuse fibrosis, tubular atrophy, necrosis, tumors in the forestomach and kidney, and death after the 6 month. It seems that long-term AAIVa exposure induced mild renal lesions could be due to the activation of the canonical or noncanonical transforming growth factor-β (TGFβ) pathway. Overall, these findings suggest that the mutagenicity and carcinogenic risk of AAIVa are very low.
先前的报告表明，马兜铃酸（AAs）暴露引起的肾毒性、突变和肿瘤发生主要归因于马兜铃酸 I（AAI）。值得注意的是，存在于许多马兜铃科植物中含量较高的马兜铃酸 IVa（AAIVa）的化学结构与 AAI 极为相似。在缺乏毒理学数据的情况下，尚不清楚 AAIVa 暴露是否会像 AAI 一样导致马兜铃酸肾病（AAN）、突变和肿瘤发生。为了回答这些问题，我们通过单次或重复长期灌胃给予 AAIVa 来处理小鼠，同时将 AAI 用作阳性对照。我们发现，单次给予 40mg/kg 的 AAIVa 没有明显的毒性。此外，在给予 1 和 10mg/kg 的 AAIVa 6 个月后，再给予 12 个月的恢复期，没有观察到小鼠发生肿瘤或死亡。AAIVa 处理的小鼠肾脏、肝脏和胃中的基因突变频率没有明显变化。有趣的是，AA 相关的突变特征（腺嘌呤到胸腺嘧啶的转换，A>T 转换）在 AAIVa 处理的小鼠中不存在。尽管如此，10mg/kg 的 AAIVa 在第 6 个月时引起了肾脏的淋巴细胞浸润和轻微的纤维增生，但在第 12 个月和第 18 个月时得到缓解。相反，AAI（阳性对照）在第 6 个月后引起严重的弥漫性纤维化、肾小管萎缩、坏死、胃和肾脏肿瘤以及死亡。似乎长期 AAIVa 暴露引起的轻度肾脏病变可能是由于经典或非经典转化生长因子-β（TGFβ）途径的激活所致。总的来说，这些发现表明 AAIVa 的致突变性和致癌风险非常低。
