Glycyrrhetinic acid might increase the nephrotoxicity of bakuchiol by inhibiting cytochrome P450 isoenzymes

Abstract

BackgroundLicorice, a popular traditional Chinese medicine (TCM), is widely used to moderate the effects (detoxification) of other herbs in TCM and often combined with Fructus Psoraleae. However, the classical TCM book states that Fructus Psoraleae is incompatible with licorice; the mechanism underlying this incompatibility has not been identified. Glycyrrhetinic acid (GA), the active metabolite of licorice, may increase the toxicity of bakuchiol (BAK), the main chemical ingredient in Psoralea corylifolia, by inhibiting its detoxification enzymes CYP450s.MethodsThe effect of concomitant GA administration on BAK-induced nephrotoxicity was investigated, and the metabolic interaction between BAK and GA was further studied in vitro and in vivo. The cytotoxicity was assessed using an MTT assay in a co-culture model of HK-2 cell and human liver microsomes (HLMs). The effect of GA on the metabolism of BAK, and on the activities of CYP isoforms were investigated in HLMs. The toxicokinetics and tissue exposure of BAK as well as the renal and hepatic functional markers were measured after the administration of a single oral dose in rats.ResultsIn vitro studies showed that the metabolic detoxification of BAK was significantly reduced by GA, and BAK was toxic to HK-2 cells, as indicated by 25∼40% decreases in viability when combined with GA. Further investigation revealed that GA significantly inhibited the metabolism of BAK in HLMs in a dose-dependent manner. GA strongly inhibits CYP3A4 and weakly inhibits CYP2C9 and CYP1A2; these CYP isoforms are involved in the metabolism of BAK. In vivo experiment found that a single oral dose of BAK combined with GA or in the presence of 1-aminobenzotriazole (ABT), altered the toxicokinetics of BAK in rats, increased the internal exposure, suppressed the elimination of BAK prototype, and therefore may have enhanced the renal toxicity.ConclusionThe present study demonstrated that GA inhibits CYP isoforms and subsequently may increase the nephrotoxicity of BAK, which underlie one of the possible mechanisms responsible for the incompatibility of Licorice with Fructus Psoraleae.

Chaihu-Shugan-San Reinforces CYP3A4 Expression via Pregnane X Receptor in Depressive Treatment of Liver-Qi Stagnation Syndrome

“…The data were also confirmed in BATMAN-TCM (http://bionet.ncpsb.org/batman-tcm) (Supplementary ). Moreover, previous studies showed that glycyrrhetinic acid (GA) was the bioactive compound after oral administration of Glycyrrhiza uralensis Fisch [37].…”

Pharmacokinetic Interactions of a Licorice Dietary Supplement with Cytochrome P450 Enzymes in Female Participants

“…In another study, an extract of G. glabra roots inhibited CYP1B1 (Sharma et al, 2017). Glycyrrhetinic acid was reported to be a potent inhibitor in vitro of CYP3A4, a weak inhibitor of CYP2C9 and CYP1A2, while altering the pharmacokinetics of the natural product bakuchiol in rats (Li et al, 2016b). Glycyrol from licorice was found to be a strong competitive inhibitor of CYP1A1 and CYP2C9 (Kim et al, 2016).…”

Nephrotoxicity of Herbal Medicine and Its Prevention

“…For example, when Shuanghuanglian injection is used in combination with glucose, insoluble particles are produced, thus affecting metabolism and causing kidney damage (Zhang et al, 2013). Radix Aconiti Kusnezoffii in combination with Radix Trichosanthis and Bulbus Fritillariae thunbergii cause a series of adverse reactions (Li, 2016;Li et al, 2016).…”