title: Glycyrrhetinic acid might increase the nephrotoxicity of bakuchiol by inhibiting cytochrome P450 isoenzymes.
abstract: BACKGROUND
  Licorice, a popular traditional Chinese medicine (TCM), is widely used to moderate the effects (detoxification) of other herbs in TCM and often combined withFructus Psoraleae. However, the classical TCM book states thatFructus Psoraleaeis 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 inPsoralea corylifolia, by inhibiting its detoxification enzymes CYP450s.
  
  
  METHODS
  The 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.
  
  
  RESULTS
  In vitrostudies 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 vivoexperiment 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.
  
  
  CONCLUSIONS
  The 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 withFructus Psoraleae.
authors.affiliation: Department of Toxicology, School of Public Health, Peking University, Beijing, China.
authors.forename: Aifang
authors.initials: A
authors.lastname: Li
authors.affiliation: Department of Toxicology, School of Public Health, Peking University, Beijing, China.
authors.forename: Nana
authors.initials: N
authors.lastname: Ma
authors.affiliation: Department of Toxicology, School of Public Health, Peking University, Beijing, China.
authors.forename: Zijing
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing, China.|State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Yuan
authors.affiliation: Beijing Institute of Pharmacology and Toxicology, Beijing, China.|State Key Laboratory of Toxicology and Medical Countermeasures, Beijing, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Toxicology, School of Public Health, Peking University, Beijing, China.|Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing, China.|Key Laboratory of State Administration of Traditional Chinese Medicine (TCM) for Compatibility Toxicology, Beijing, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
keywords: Bakuchiol; Cytochrome p450; Glycyrrhetinic acid; Nephrotoxicity; Toxicokinetics