Toxic Evaluations of Calea phyllolepis Extracts Standardized on 6‐epi‐β‐Verbesinol Coumarate and Its In Silico Prediction of the Toxicity

Medicinal plants are traditionally used in folk medicine. Still, there is a misconception about the safety/efficacy of natural treatments, which results in few studies on the toxic, genotoxic, and mutagenic potential of plants. Therefore, this work investigates the toxicological and mutagenic potential of an ethanolic extract and fractions of Calea phyllolepis leaves using Caenorhabditis elegans and Salmonella typhimurium assays. Through the results obtained, it was verified that only the hexane fraction induced toxicity in C. elegans , affecting the survival and development of nematodes. In addition, this fraction was mutagenic through the S. typhimurium assay only in the presence of metabolization. A previous study pointed out that the major compound identified in the hexane fraction, 6‐ epi ‐β‐verbesinol coumarate, was responsible for the cytotoxic effects. Probably due to the fragility of the carbon–oxygen bond of the 6‐ epi ‐β‐verbesinol coumarate, this substance undergoes degradation, generating verbesinol (sesquiterpene) and coumaric acid (phenolic acid) in the body in vivo as active metabolites. Based on the in silico predictions for 6‐ epi ‐β‐verbesinol coumarate metabolism and toxicity, 21 metabolites and 7 potentially mutagenic products were identified, belonging to three classes: epoxides (three metabolites), α,β‐unsaturated carbonylated compounds (one metabolite), and simple aldehydes.