Detoxification and underlying mechanisms towards toxic alkaloids by Traditional Chinese Medicine processing: A comprehensive review

Alkaloids gained long-lasting interest worldwide for their extraordinary therapeutic effects of analgesic, anti-inflammation, and anti-tumor, offering a rich source for lead compound design and new drug discovery. However, some of these alkaloids possess intrinsic toxicity. Processing (Paozhi) is a pre-processing step before herbal medicines' application in traditional Chinese medicine (TCM) clinics, which has been employed for centuries to mitigate the toxicity of alkaloid-rich TCMs. To explore the toxicity phenotypes, chemical basis, mode of action, detoxification processing methods, and underlying mechanisms, we can gain crucial insights into the safe and rational use of these toxic alkaloid-rich herbs, which have the great potential to offer new strategies for drug discovery and development, and help improve the quality of life for millions of people. Literatures published or early accessed until December 31, 2023, were retrieved from databases including PubMed, Web of Science, and CNKI. The following keywords, such as "toxicity", "alkaloid", "detoxification", "processing", "traditional Chinese medicine", "medicinal plant", "plant", were used combined or separately for screening. Toxicity of alkaloids in TCM including hepatotoxicity, nephrotoxicity, neurotoxicity, cardiotoxicity, and other forms of toxicity, primarily induced by pyrrolizidines, quinolizidines, isoquinolines, indoles, pyridines, terpenoids, and amines. Whether the toxic-alkaloid enriched part is limited, heat-sensitive, toxic alkaloids are also the therapeutic components, are critical factors for choosing appropriate detoxification processing methods. The mechanisms towards alkaloid-toxin detoxification includes physical removal, chemical decomposition or transformation, as well as biological modifications. Through this exploration, we review the toxic alkaloids and the mechanisms underlying their toxicity, possessing methods to reduce toxicity, and unravel the intricate mechanisms behind detoxification, offering insights into the quality control of herbs containing toxic alkaloids, safe and rational use of alkaloid-rich TCMs in clinics, new strategies for drug discovery and development, and help improve the quality of life for millions of people.