Drug-induced mitochondrial dysfunction has forced the withdrawal of major drugs used to treat diabetes (e.g., troglitazone) and hyperlipidemia (e.g., cerivastatin). Nearly half of the drugs with hepatotoxicity and cardiotoxicity-associated FDA Black Box Warnings interfere with mitochondrial function. While the pharmaceutical industry has begun to evaluate potential mitochondrial liability of new therapeutic agents, the plethora of phytochemicals in botanical dietary supplements (BDS) have not been examined. Extracts from 352 plants used in traditional Chinese, Ayurvedic, and Western Herbal Medicine were evaluated for their potential to disrupt mitochondrial function. Blue cohosh [Caulophyllum thalictroides L. (Berberidaceae)] extract, typically used as an antispasmodic, menstrual flow stimulator, and abortifacient, exhibited mitochondriotoxic activity. This toxicity is particularly noteworthy given a report indicating that approximately 64% of US midwives have used blue cohosh to induce labor. Perinatal stroke, acute myocardial infarction, congestive heart failure, multiple organ injury, and neonatal shock have been associated with blue cohosh tincture/dietary supplements consumption. The potential link between mitochondrial disruption and idiosyncratic herbal intoxication prompted further examination of blue cohosh components on cellular respiration. Three saponins (cauloside A, cauloside C, and saponin PE) exhibited mitochondriotoxic activity in a concentration- and time-dependent manner. Upon treatment, a rapid burst in cellular oxygen consumption was followed by a dramatic decrease in respiration. These constituents impair mitochondrial function by disrupting membrane integrity. Thus, herbal supplements must be carefully evaluated for potential adverse effects on mitochondrial function.
