Limonin: A Review of Its Pharmacology, Toxicity, and Pharmacokinetics

Abstract

Limonin is a natural tetracyclic triterpenoid compound, which widely exists in Euodia rutaecarpa (Juss.) Benth., Phellodendron chinense Schneid., and Coptis chinensis Franch. Its extensive pharmacological effects have attracted considerable attention in recent years. However, there is no systematic review focusing on the pharmacology, toxicity, and pharmacokinetics of limonin. Therefore, this review aimed to provide the latest information on the pharmacology, toxicity, and pharmacokinetics of limonin, exploring the therapeutic potential of this compound and looking for ways to improve efficacy and bioavailability. Limonin has a wide spectrum of pharmacological effects, including anti-cancer, anti-inflammatory and analgesic, anti-bacterial and anti-virus, anti-oxidation, liver protection properties. However, limonin has also been shown to lead to hepatotoxicity, renal toxicity, and genetic damage. Moreover, limonin also has complex impacts on hepatic metabolic enzyme. Pharmacokinetic studies have demonstrated that limonin has poor bioavailability, and the reduction, hydrolysis, and methylation are the main metabolic pathways of limonin. We also found that the position and group of the substituents of limonin are key in affecting pharmacological activity and bioavailability. However, some issues still exist, such as the mechanism of antioxidant activity of limonin not being clear. In addition, there are few studies on the toxicity mechanism of limonin, and the effects of limonin concentration on pharmacological effects and toxicity are not clear, and no researchers have reported any ways in which to reduce the toxicity of limonin. Therefore, future research directions include the mechanism of antioxidant activity of limonin, how the concentration of limonin affects pharmacological effects and toxicity, finding ways to reduce the toxicity of limonin, and structural modification of limonin—one of the key methods necessary to enhance pharmacological activity and bioavailability.

Limonin Enhances the Antifungal Activity of Eugenol Nanoemulsion against Penicillium Italicum In Vitro and In Vivo Tests

“…It has been reported for various biological activities like antiviral, antifungal, antibacterial, anticancer and antimalarial, etc. [ 38 , 39 , 40 ]. However, to our knowledge, there have been no reports on the application of limonin in reducing postharvest blue mold of citrus fruit.…”

“…Our results showed that the addition of a low dose of limonin to EG nanoemulsion could significantly improve the antifungal activity against P. italicum in vitro, suggesting that limonin and eugenol played a synergistic effect. Limonin has been reported to interfere with the transmission of signals between microbial cells and effectively inhibit intercellular communication [ 39 ]. Therefore, limonin probably reduced the adaptability of fungal cells to external pressures and enhance their sensitivity to eugenol.…”

Natural Anti-Inflammatory Compounds as Drug Candidates for Inflammatory Bowel Disease

“…Limonin is a secondary metabolite with high biological activity in plants. It is present mainly in the fruits of Rutaceae plants, such as navel oranges, citruses, oranges, and grapefruits (Zhang et al, 2015;Wang et al, 2018c;Fan et al, 2019). The content in the core (seed) of the fruit is higher, while the content in the peel is low.…”

Chemical Constituents from Citrus changshan‐huyou and Their Anti‐Inflammatory Activities

“…It is worth mentioning that the most abundant compound is limonin ( 1 ; 0.5 g), with 2.27 % yield in the crude AcOEt extract. Literature survey indicated that limonin has extensive pharmacological effects, [24] especially the anti‐inflammatory activity by the inhibition of TNF‐ α release, and the regulation of TLR4/NF‐ κ B pathway [25] . In order to obtain more limonin‐like compounds for further study of anti‐inflammatory activities, we have carried out a chemical transformation of limonin through reduction reactions with different reductants such as sodium borohydride (NaBH 4 ), sodium cyanoborohydride (NaBH 3 CN) and lithium aluminum hydride (LiAlH 4 ) [26] .…”