Genotoxicity and Safety Pharmacology Studies of Indole Alkaloids Extract from Leaves of Alstonia scholaris (L.) R. Br.

doi:10.1007/s13659-020-00242-4

应用天然产物 ›› 2020, Vol. 10 ›› Issue (3): 119-129.DOI: 10.1007/s13659-020-00242-4

Genotoxicity and Safety Pharmacology Studies of Indole Alkaloids Extract from Leaves of Alstonia scholaris (L.) R. Br.

Yun-Li Zhao^1,3, Min Su², Jian-Hua Shang^2,3, Xia Wang², Guang-Lei Bao², Jia Ma², Qing-Di Sun⁴, Fang Yuan², Jing-Kun Wang², Xiao-Dong Luo^1,3

1 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, People's Republic of China;
2 Yunnan Institute of Medical Material, Kunming 650111, People's Republic of China;
3 Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, People's Republic of China;
4 Jiangsu Nhwa Pharmaceutical Co., Ltd, Xuzhou 221009, People's Republic of China

收稿日期:2020-03-19 修回日期:2020-04-17 出版日期:2020-06-24 发布日期:2020-06-02
通讯作者: Xiao-Dong Luo, Jing-Kun Wang
基金资助:
The authors are grateful to Yunnan Major Science and Technology Project (2019ZF003, 2019FY003004),the National Key Research and Development Program of China (2017YFC1704007), and the general program of applied basic research of Yunnan province (2019FB116) for partial financial support.

Genotoxicity and Safety Pharmacology Studies of Indole Alkaloids Extract from Leaves of Alstonia scholaris (L.) R. Br.

Yun-Li Zhao^1,3, Min Su², Jian-Hua Shang^2,3, Xia Wang², Guang-Lei Bao², Jia Ma², Qing-Di Sun⁴, Fang Yuan², Jing-Kun Wang², Xiao-Dong Luo^1,3

1 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, People's Republic of China;
2 Yunnan Institute of Medical Material, Kunming 650111, People's Republic of China;
3 Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming 650091, People's Republic of China;
4 Jiangsu Nhwa Pharmaceutical Co., Ltd, Xuzhou 221009, People's Republic of China

Received:2020-03-19 Revised:2020-04-17 Online:2020-06-24 Published:2020-06-02
Contact: Xiao-Dong Luo, Jing-Kun Wang
Supported by:
The authors are grateful to Yunnan Major Science and Technology Project (2019ZF003, 2019FY003004),the National Key Research and Development Program of China (2017YFC1704007), and the general program of applied basic research of Yunnan province (2019FB116) for partial financial support.

摘要/Abstract

摘要： Indole alkaloids extract (IAAS) was prepared from leaves of Alstonia scholaris (L.) R. Br., an evergreen tropical plant widely distributed throughout the world. This plant has been used historically by the Dai ethnic people of China to treat respiratory diseases. This study evaluated the genotoxicity and safety pharmacology of IAAS to support clinical use. The bacterial reverse mutation (Ames) test, in vitro mammalian chromosomal aberration test, and in vivo mammalian erythrocyte micronucleus (MN) test were performed to evaluate genotoxicity. Mice were administered IAAS (240, 480, or 960 mg/kg bw) once orally to observe adverse central nervous system effects. Furthermore, beagle dogs were administered IAAS (10, 30, 60 mg/kg bw) once via the duodenum to evaluate its effects on the cardiovascular and respiratory systems. IAAS with or without S9-induced metabolic activation showed no genotoxicity in the Ames test up to 500 μg/plate, in the mammalian chromosomal aberration test up to 710 μg/mL, or in the MN test up to 800 mg/kg bw. No abnormal neurobehavioral effects were observed in mice following treatment with up to 960 mg/kg bw of IAAS. Moreover, blood pressure, heart rate, electrocardiogram parameters, and depth and rate of breathing in anesthetized beagle dogs did not differ among the IAAS doses or from the vehicle group. These data indicated that IAAS did not induce mutagenicity, clastogenicity, or genotoxicity, and no pharmaco-toxicological effects were observed in the respiratory, cardiovascular, or central nervous systems. Our results increased understanding of safety considerations associated with IAAS, and may indicate that IAAS is a possible drug candidate.

关键词: Alstonia scholaris, Indole alkaloids extract, Genotoxicity, Safety pharmacology, Mice, Dogs

Abstract: Indole alkaloids extract (IAAS) was prepared from leaves of Alstonia scholaris (L.) R. Br., an evergreen tropical plant widely distributed throughout the world. This plant has been used historically by the Dai ethnic people of China to treat respiratory diseases. This study evaluated the genotoxicity and safety pharmacology of IAAS to support clinical use. The bacterial reverse mutation (Ames) test, in vitro mammalian chromosomal aberration test, and in vivo mammalian erythrocyte micronucleus (MN) test were performed to evaluate genotoxicity. Mice were administered IAAS (240, 480, or 960 mg/kg bw) once orally to observe adverse central nervous system effects. Furthermore, beagle dogs were administered IAAS (10, 30, 60 mg/kg bw) once via the duodenum to evaluate its effects on the cardiovascular and respiratory systems. IAAS with or without S9-induced metabolic activation showed no genotoxicity in the Ames test up to 500 μg/plate, in the mammalian chromosomal aberration test up to 710 μg/mL, or in the MN test up to 800 mg/kg bw. No abnormal neurobehavioral effects were observed in mice following treatment with up to 960 mg/kg bw of IAAS. Moreover, blood pressure, heart rate, electrocardiogram parameters, and depth and rate of breathing in anesthetized beagle dogs did not differ among the IAAS doses or from the vehicle group. These data indicated that IAAS did not induce mutagenicity, clastogenicity, or genotoxicity, and no pharmaco-toxicological effects were observed in the respiratory, cardiovascular, or central nervous systems. Our results increased understanding of safety considerations associated with IAAS, and may indicate that IAAS is a possible drug candidate.

Key words: Alstonia scholaris, Indole alkaloids extract, Genotoxicity, Safety pharmacology, Mice, Dogs

Yun-Li Zhao, Min Su, Jian-Hua Shang, Xia Wang, Guang-Lei Bao, Jia Ma, Qing-Di Sun, Fang Yuan, Jing-Kun Wang, Xiao-Dong Luo. Genotoxicity and Safety Pharmacology Studies of Indole Alkaloids Extract from Leaves of Alstonia scholaris (L.) R. Br.[J]. 应用天然产物, 2020, 10(3): 119-129.

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Genotoxicity and Safety Pharmacology Studies of Indole Alkaloids Extract from Leaves of Alstonia scholaris (L.) R. Br.

Genotoxicity and Safety Pharmacology Studies of Indole Alkaloids Extract from Leaves of Alstonia scholaris (L.) R. Br.

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