Untargeted Safety Pharmacology Screen of Blood-Activating and Stasis-Removing Patent Chinese Herbal Medicines Identified Nonherbal Ingredients as a Cause of Organ Damage in Experimental Models

Xinyan Liu; Rui Shao; Xinyue Yang; Guangxu Xiao; Shuang He; Yuxin Feng; Yan Zhu

doi:10.3389/fphar.2019.00993

Untargeted Safety Pharmacology Screen of Blood-Activating and Stasis-Removing Patent Chinese Herbal Medicines Identified Nonherbal Ingredients as a Cause of Organ Damage in Experimental Models

Front Pharmacol. 2019 Sep 12:10:993. doi: 10.3389/fphar.2019.00993. eCollection 2019.

Authors

Xinyan Liu^{1

2}, Rui Shao^{1

2}, Xinyue Yang^{1

2}, Guangxu Xiao^{1

2}, Shuang He^{1

2}, Yuxin Feng^{1

2}, Yan Zhu^{1

2

3}

Affiliations

¹ Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
² Research and Development Center of TCM, Tianjin International Joint Academy of Biotechnology & Medicine, Tianjin, China.
³ Molecular Cardiology Research Institute, Tufts Medical Center and Tufts University School of Medicine, Boston, MA, United States.

Abstract

Blood activation and stasis removal from circulation is a central principle for treatment of syndromes related to cerebral and cardiovascular diseases in Chinese herbal medicine. However, blood-activating and stasis-removing patent Chinese herbal medicine (BASR-pCHM) widely used with or without prescription in China and elsewhere are highly variable in composition and manufacture standard, making their safety assessment a challenging task. We proposed that an integrated evaluation of multiple toxicity parameters of BASR-pCHM would provide critical reference and guidelines for their safe clinical application. Examination of standardized extracts from 58 compound BASR-pCHM in vivo in VEGFR2-luc mice and in vitro in cardiac, renal, and hepatic cells identified Naoluotong capsule (NLTC) as a potent organ/cell damage inducer. Composition analysis revealed that NLTC was the one that contained nonherbal ingredients among the BASR-pCHM collection. In vivo and in vitro experiments confirmed that NLTC, as well as its chemical supplement tolperisone hydrochloride, caused organ and cell damage by reducing cell viability, mitochondrial mass/activity, while the NLTC herbal components did not. Taken together, our study showed that safety evaluation of patent herbal medicines already on market is still necessary and urgently needed. In addition, chemical/herbal interactions should be considered as an important contributor of potential toxicity when evaluating the safety of herbal medicine.

Keywords: Chinese herbal medicine; blood-activating and stasis-removing medicines; herbal–drug interaction; organ damage; safety pharmacology; toxicity.