Gallic Acid Exhibits Risks of Inducing Muscular Hemorrhagic Liposis and Cerebral Hemorrhage—Its Action Mechanism and Preventive Strategy

• Published in: Phytotherapy research 2015-02, Vol.29 (2), p.267-280
• Main Authors: Hsieh, Chiu‐Lan, Lin, Chien‐Hong, Wang, Hui‐Er, Peng, Chiung‐Chi, Peng, Robert Y
• Format: Article
• Language: English
• Subjects: acetylcysteine; Acetylcysteine - pharmacology; adverse effects; Animals; carnitine; Cerebral Hemorrhage - chemically induced; Chick Embryo; chickens; chicks; creatine kinase; cytochrome-c oxidase; Dietary Supplements; Dose-Response Relationship, Drug; Dyslipidemias - chemically induced; folic acid; gallic acid; Gallic Acid - adverse effects; Gallic Acid - pharmacology; gene expression regulation; genes; genes CPT1 and vegf; glutathione; Glutathione - pharmacology; hemorrhage; hemorrhagic liposis; hydrogen peroxide; hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; lactate dehydrogenase; malondialdehyde; mechanism of action; muscles; muscular diseases; Neck Muscles - drug effects; Neck Muscles - pathology; nitric oxide; phytotherapy; risk; superoxide dismutase; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor Receptor-2 - metabolism; vitamin E; Vitamin E - pharmacology
• ISSN: 0951-418X; 1099-1573
• DOI: 10.1002/ptr.5249

Gallic acid (3,4,5‐trihydroxybenzoic acid) (GA) occurs in many plants. The adverse effects of GA are seldom cited. GA (6–14 μM) provoked the hemorrhagic liposis of the cervical muscles and intracranial hemorrhage. The cause of these pathological events and the method for prevention are still lacking. Using the chicken embryo model and some selected nutraceutics such as folate, glutathione (GSH), N‐acetylcysteine, and vitamin E (Vit E), we carried out this study. Results revealed that the action mechanism of GA involved (i) inducing hypoxia with upregulated gene hif‐1α and downregulated ratio vegf‐r2/vegf‐a, leading to dys‐vascularization and myopathy; (ii) impairing cytochrome c oxidase; (iii) stimulating creatine kinase and lactate dehydrogenase release; (iv) eliciting carnitine accumulation and liposis via downregulating gene CPT1; (v) suppressing superoxide dismutase and stimulating NO, H₂O₂, and malondialdehyde; and (vi) depleting erythrocytic and tissue GSH, resulting in hemorrhage. When both Vit E and GSH were applied to the day 1 chicks, a better alleviation effect was revealed. Conclusively, GA potentially exhibits adverse effect by eliciting hemorrhagic liposis of cervical muscles and cerebral hemorrhage. Supplementation with GSH, Vit E, and N‐acetylcysteine is able to ameliorate these adverse effects, warranting the importance of restricting the clinical phytotherapeutic doses of GA and related compounds. Copyright © 2014 John Wiley & Sons, Ltd.