Abstract

Pterodon pubescens Benth. is widely used in folk medicine for the treatment of inflammatory conditions, with the activity attributed to the compounds with a vouacapan moiety, however, few studies report the toxicological evaluation of the extract and safety issues related to the species. Herein the non-clinical toxicity, in in vivo and in vitro tests, of dichloromethane crude extract of Pterodon pubescens fruits (PPE) and vouacapan diterpene furan isomer´s mixture (1:1) 6α-hydroxy-7β-acetoxy-vouacapan-17β-oate methyl ester and 6α-acetoxy-7β-hydroxy-vouacapan-17β-oate methyl ester isomers (VDFI mixture) is reported. Toxicological evaluation of 110-day repeated dose oral toxicity study, as hematological, biochemical, and histopathological parameters demonstrated that animals (male and female Wistar rats) treated with PPE presented no signs of toxicity, nevertheless daily high dose administration (500 mg/Kg) altered the metabolic homeostasis of animals that manifested microgoticular hepatic steatosis. Biochemical and histopathological results of animals (female Swiss mice) treated daily with VDFI mixture, at the highest dose (300 mg/Kg), indicated liver toxicity in one animal causing acute hepatotoxicity. Alkaline Comet assay demonstrated that PPE and VDFI mixture increased the percentage of DNA fragmentation without interfering with the tail moment parameter, but only VDFI mixture (30 µg/mL) presented statistical difference. In the micronucleus induction test, PPE and VDFI mixture did not demonstrate mutagenic potential. Our data provide evidence for the safety use of PPE and VDFI mixture in lower doses enabling further clinical studies and the development of herbal medicine.

摘要

Pterodon pubescens Benth. 在民间医学中广泛用于治疗炎症性疾病，其活性归因于具有 vouacapan 部分的化合物，然而，很少有研究报告提取物的毒理学评估和与该物种相关的安全问题。在此，在体内和体外试验中，毛毛蕨果实 (PPE) 和 vouacapan 二萜呋喃异构体混合物 (1:1) 6 α -hydroxy -7 β -acetoxy-vouacapan的二氯甲烷粗提物的非临床毒性-17 β -oate 甲酯和 6α-acetoxy-7 β -hydroxy-vouacapan-17 β报告了-oate甲酯异构体（VDFI混合物）。110 天重复剂量口服毒性研究的毒理学评价，血液学、生化和组织病理学参数表明，用 PPE 治疗的动物（雄性和雌性 Wistar 大鼠）没有出现毒性迹象，但每日高剂量给药（500 mg/Kg）改变了表现出微小肝脂肪变性的动物的代谢稳态。每天用最高剂量 (300 mg/Kg) 的 VDFI 混合物处理动物（瑞士雌性小鼠）的生化和组织病理学结果表明，一只动物的肝毒性导致急性肝毒性。碱性彗星试验表明，PPE 和 VDFI 混合物增加了 DNA 片段化的百分比，而不会干扰尾矩参数，但只有 VDFI 混合物 (30 µg/mL) 存在统计学差异。在微核诱导试验中，PPE 和 VDFI 混合物未表现出诱变潜力。我们的数据为低剂量使用 PPE 和 VDFI 混合物的安全性提供了证据，使进一步的临床研究和草药的开发成为可能。