Sub-Chronic Toxicological Evaluation of the Sesquiterpene Lactone-enriched Fraction of Tithonia diversifolia (Hemsley) A. Gray in Experimental Rats

The growing interest in herbal and alternative medicines demands information on the toxicity risk assessment of the various plant extracts used in traditional medicines. The presence of a potential toxic phytochemicals in Tithonia diversifolia extracts necessitates toxicological evaluation of its biologically active constituents. The study evaluated the in vivo sub-chronic toxicity of the moderately polar fractions of T. diversifolia in a rat model. The ethyl acetate soluble portion from the methanol extract was separated by vacuum liquid chromatographic method. Three-dose levels- an observed adverse effect level (OAEL) of 2000 mg/kg, a no-observed adverse effect level (NOAEL) of 80 mg/kg and an intermediate dose of 500 mg per kg body weight of rats per day- were selected for a 28-day repeated dosing for the sub-chronic toxicological evaluation. The LC-MS dereplication of the active fractions showed the presence of sesquiterpene lactones such as diversifolin, diversifolin methylether, tagitinin A, tagitinin C-F, woodhousin, and orizatin and many unidentified peaks. There was a significant reduction (p < 0.05) in the weights of and food consumption by the rats dosed with OAEL of the fraction on week 1 which normalized during the subsequent weeks of the study. The histopathological examination showed a mild necrosis and degeneration of hepatocytes in the centrilobular areas of the rats treated with OAEL of the active VLC fraction. There was no T. diversifolia-related adverse toxicological events in rats with a 2000 mg/kg/day when dosed orally for 28 days.