title: Modulation of the pentose phosphate pathway alters phase I metabolism of testosterone and dextromethorphan in HepG2 cells.
abstract: OBJECTIVE
  The pentose phosphate pathway (PPP) is involved in the activity of glucose-6-phosphate dehydrogenase (G6PD) and generation of NADPH, which plays a key role in drug metabolism. The aim of this study was to investigate the effects of modulation of the PPP on drug metabolism capacity in vitro.
  
  
  METHODS
  A pair of hepatic cell lines, ie, the cancerous HepG2 cells and normal L02 cells, was used. The expression of CYP450 enzymes, p53 and G6PD in the cells were analyzed. The metabolism of testosterone (TEST, 10 μmol/L) and dextromethorphan (DEM, 1 μmol/L), the two typical substrates for CYP3A4 and CYP2D6, in the cells was examined in the presence of different agents.
  
  
  RESULTS
  Both the expression and metabolic activities of CYP3A4 and CYP2D6 were considerably higher in HepG2 cells than in L02 cells. The metabolism of TEST and DEM in HepG2 cells was dose-dependently inhibited by the specific CYP3A4 inhibitor ketoconazole and CYP2D6 inhibitor quinidine. Addition of the p53 inhibitor cyclic PFT-α (5, 25 μmol/L) in HepG2 cells dose-dependently enhanced the metabolism of DEM and TEST, whereas addition of the p53 activator NSC 66811 (3, 10, 25 μmol/L) dose-dependently inhibited the metabolism. Furthermore, addition of the G6PD inhibitor 6-aminonicotinamide (5, 15 μmol/L) in HepG2 cells dose-dependently inhibited the metabolism of DEM and TEST, whereas addition of the PPP activity stimulator menadione (1, 5, 15 μmol/L) dose-dependently enhanced the metabolism.
  
  
  CONCLUSIONS
  Modulation of p53 and the PPP alters the metabolism of DEM and TEST, suggesting that the metabolic flux pattern of PPP may be closely involved in drug metabolism and the individual variance.
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Wen-jing
authors.initials: WJ
authors.lastname: Xiao
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Ma
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Ge
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Wen-juan
authors.initials: WJ
authors.lastname: Xia
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Mao
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Run-bin
authors.initials: RB
authors.lastname: Sun
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Xiao-yi
authors.initials: XY
authors.lastname: Yu
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Ji-ye
authors.initials: JY
authors.lastname: Aa
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Guang-ji
authors.initials: GJ
authors.lastname: Wang
mesh_terms: D045744:Cell Line, Tumor; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D003915:Dextromethorphan / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D050216:Metabolic Detoxication, Phase I / Q000502:physiology*; D010427:Pentose Phosphate Pathway / Q000502:physiology*; D013739:Testosterone / Q000378:metabolism*
chemical_list: D013739:Testosterone; D003915:Dextromethorphan; D051544:Cytochrome P-450 CYP3A