title: Effect of Chinese herbs on CYP3A4 activity and expression in vitro.
abstract: BACKGROUND
  Traditional Chinese Medicine (TCM) has become more popular among cancer patients in the Western world, who often use Chinese herbs as adjuvant therapy to reduce the adverse effects of conventional chemotherapy. However, pharmacokinetic (PK) interactions between Chinese herbs and anticancer drugs can occur and have dramatic consequences for these patients. Currently, only a few possible PK interactions between Chinese herbs and conventional Western drugs have been documented.
  
  
  OBJECTIVE
  Since the drug-metabolizing enzyme cytochrome P450 3A4 (CYP3A4) contributes to most of the PK interactions with (anticancer) drugs, the effect of four Chinese herbs (Oldenlandia diffusa, Codonopsis tangshen, Rehmannia glutinosa and Astragalus propinquus) on the activity and expression of CYP3A4 was investigated in vitro.
  
  
  METHODS
  Ethanol and water-ethanol extracts of the four Chinese herbs were prepared from raw material. CYP3A4 inhibition was assessed by the use of Supersomes™ in a fluorescence assay. Furthermore, CYP3A4 induction was evaluated in a human pregnane X receptor (hPXR)-mediated CYP3A4 reporter gene assay and a quantitative real time PCR assay, both in human colon adenocarcinoma-derived LS180 cells (LS180).
  
  
  RESULTS
  Extracts of Oldenlandia diffusa, Codonopsis tangshen, Rehmannia glutinosa and Astragalus propinquus inhibited CYP3A4 in human CYP3A4 Supersomes™ (IC50 values: 17-83 µg/mL). Oldenlandia diffusa and Rehmannia glutinosa significantly induced PXR-mediated CYP3A4 (p<0.001). Oldenlandia diffusa also significantly induced CYP3A4 mRNA levels (p<0.001 at 250 µg/mL).
  
  
  CONCLUSIONS
  Concomitant use of Oldenlandia diffusa and Rehmannia glutinosa could result in induction of CYP3A4, leading to a reduced efficacy of drugs that are CYP3A4 substrates and have a narrow therapeutic window. Because of the possible enhanced toxicity caused by CYP3A4 inhibition, clinical effects of CYP3A4 inhibition by Astragalus propinquus and Codonopsis tangshen must also be taken into account. In conclusion, herb-drug interactions between Chinese herbs and various CYP3A4 substrates can occur. Further research to investigate the clinical relevance of the interactions caused by Oldenlandia diffusa, Codonopsis tangshen, Rehmannia glutinosa and Astragalus propinquus is required.
authors.affiliation: Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: Lau
authors.forename: K D
authors.initials: KD
authors.lastname: Mooiman
authors.forename: R F
authors.initials: RF
authors.lastname: Maas-Bakker
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: J H M
authors.initials: JH
authors.lastname: Schellens
authors.forename: I
authors.initials: I
authors.lastname: Meijerman
mesh_terms: D027883:Astragalus Plant; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D029745:Codonopsis; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004365:Drugs, Chinese Herbal; D006801:Humans; D032067:Oldenlandia; D010936:Plant Extracts / Q000494:pharmacology*; D032267:Rehmannia
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D004365:Drugs, Chinese Herbal; D010936:Plant Extracts; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human
keywords: CYP3A4; Cytochrome P450 3A4; Herb–drug interactions; Oldenlandia diffusa; PD; PK; Pharmacokinetics; Rehmannia glutinosa; TCM; Traditional Chinese Medicine; cytochrome P450 3A4; hPXR; human pregnane X receptor; pharmacodynamic; pharmacokinetic