Coptidis Rhizoma: a comprehensive review of its traditional uses, botany, phytochemistry, pharmacology and toxicology

Wang, Jin; Wang, Lin; Lou, Guan-Hua; Zeng, Hai-Rong; Hu, Ju; Huang, Qin-Wan; Peng, Wei; Yang, Xiang-Bo

CR has been banned in Singapore in recent decades because of the suggestion that berberine aggravated jaundice and kernicterus in neonates with glucose-6-phosphate dehydrogenase deficiency (Wong 1980) . In 2012, researchers found no organ toxicity or electrolyte imbalance in 20 patients administered with CR at a daily dose of 3 g for 1055 patient-days (Linn et al. 2012) . In 2016, the ban of Chinese herbal medicines rich in berberine was officially lifted. Nevertheless, toxicity cannot be ignored. An acute toxicity study showed that the oral medial lethal dose (LD 50 ) of the fibrous roots of CR was greater than 7000 mg/kg body weight in Kunming mice. A sub-chronic toxicity study showed that the no-observed-adverse effect level (NOAEL) was 1.88 g/kg body weight in rats, whereas 3.76 g/kg body weight resulted in liver and lung damage. An Ames test, a mouse micronucleus test, and a mouse sperm abnormality test provided negative results (Ning et al. 2015) . The median acute oral lethal dose of the CRE was 2.95 g/kg in mice; however, the alkaloid-rich extract was much more toxic than the total extract of CR (Ma et al. 2010) . In another study, the LD 50 values of four alkaloids (berberine, coptisine, palmatine and epiberberine) were determined as 713.57, 852.12, 1533.68 and 1360 mg/kg, respectively. Likewise, the cytotoxicity of berberine was the highest and that of palmatine was the lowest toward HepG2 and 3T3-L1 cells. In a subchronic toxicity study, no mortality or morbidity was observed (Yi et al. 2013) . To determine the NOAEL and the toxicity of CR, rats received repeated oral administration of CR for 13 weeks. No mortality or remarkable clinical signs were observed during this 13-week study. The NOAEL of CR was determined as 667 mg/kg/day for male rats and 2000 mg/kg/day for female rats (Lee et al. 2014) . Oral berberine has caused respiratory failure, extrapyramidal system reactions, severe arrhythmia, liver function injury and even death in clinics in China , which as believed to caused by its inhibitory effect on the human eag-related gene (hERG) potassium channel and induction of mitochondrial dysfunction (Pereira et al. 2008; Schramm et al. 2011) . Furthermore, the authors reported that an AChE inhibitor significantly increased the acute toxicity of the CRE, whereas a cholinesterase reactivator significantly decreased the acute toxicity. Therefore, the authors suggested that the acute toxicity of the oral CR extract was related to AChE inhibition (Ma et al. 2011 ) Taking these findings together, we concluded that the toxic constituents of CR were the alkaloids, mainly berberine. However, the toxic mechanism of the CR alkaloids may be complicated and remains to be determined. The currently recommended doses of CR alkaloids and CR consumption are relatively safe (Ho et al. 2014) . In fact, CR is seldom used alone in clinics; instead, it is usually prescribed with other medicines that could reduce its toxic effect.