| Ferulic acid (C10H10O4,3-methoxy-4-hydroxy-cinnamate acid, FA), is widely distributed in herb drugs and Chinese formulas such as Ligusticum, Chuanxiong and Chaihu-Sugan-San, usually used as food supplements or herbal medicine in countries or areas accepting the theory of Traditional Chinese Medicine (TCM). With the anti-oxidant, anti-atherogenic, anti-platelet clotting, anti-inflammatory, lipid-lowering, cholesterol biosynthesis inhibitory and analgesic effects, FA has the potential to be developed into an effective pure compound to prevention and treatment of cardiovascular diseases. Presently, SF has been approved by State Food and Drugs Administration of China (SFDA) as a clinical therapy of cardiovascular and cerebrovascular diseases. The early report showed SF can inhibit CYP450s activity in mice. Recent studies confirmed the chemical hybrid molecules of FA and tacrine affected CYP1A1,2B1,3A2expression and activity, and reduced its liver toxicity compared with tacrine molecular in rats. However, the effect of SF on the pharmacokinetics of other coadministrated drugs has seldom reported.Pharmacogenetics studies found that the herb drug-drug interactions were associated with gene variants of the CYPs, transporters, drug receptors. Pharmacogenomics investigations confirmed the genetic polymorphism of human pregnane X receptor (hPXR) and cytochrome P450oxidoreductase (POR) also involved in the drug-drug interactions.Based on these informations, this study is aimed to investigate the effect of ferulic acid on the activities of several important CYPs and transporters through pharmacogenomics methods, and evaluate roles and clinical significance of genetic polymorphisms of CYP2B6, PXR, and POR involved in the metabolic inducibility of bupropion hydroxylation by sodium ferulate (SF) administration. The present series studies found that:1) Within certain concentration range, SF significantly increased the promoter activity of CYP3A4,2C9,2B6, MDR and MRP2-ER-8in Luciferase reporter assay, and showed the inducibility of CYPs and transporters.2) After SF treatment, Cmax of bupropion was significantly increased, while the Tmax of bupropion and AUC (0-8), T1/2and Cmax of hydroxybupropion were significantly decreased, and the AUC ratio (AUC_hyd/AUC_bup), which represents the metabolic activity of bupropion into hydroxybupropion, markedly increased.3) The distribution frequencies of CYP2B6516GG, GT, and TT were:0.580,0.333,0.087, respectively, and785AA, AG, GG were:0.473,0.400, and0.127, respectively. The frequencies of CYP2B6*1/*1,*1/*6,*6/*6,*1/*4,*4/*4,*1/*9,*9/*9,*4/*6, and*6/*9were:0.480,0.253,0.053,0.106,0.007,0.007,0.007,0.060, and0.027, respectively.4) After SF treatment, AUC ratio of CYP2B6*1/*1and*1/*6individuals significantly increased, while that of*6/*6genotype did not show significant changes. CL/F of bupropion had an increasing trend, but there was no significant alteration with SF administration.5) The mutation frequencies of POR-173C>A,-208C>T,1508C>T, and6593A>G were:0.000,0.000,0.377, and0.500, respectively. AUC ratio of POR6593AG and GG subjects showed statistically significant difference compared with AA genotypes by SF administration.6) The frequencies of NR1I2alleles-25385T,-24113A,-24020(-), g.7635G and g.8055T were0.283,0.181,0.208,0.522, and0.625, respectively. Among NR1I2-25385C>T,-24113G>A, and-24020[GAGAAG]>(-) and between g.7635A>G and g.8055C>T displayed significant linkage disequilibrium.5SNPs of NR1I2gene displayed18haplotypes:TGAAC, TGAGC, TGAGT TGTGT TATAC TATAT TATGC TATGT CGAAC CGAAT CGAGC CGAGT CGTAC CGTGT, CAAAC, CAAGT, CATGC, and CATGT, and distribution frequencies were:0.042857,0.014989,0.023883,0.005310,0.028007,0.000565,0.045795,0.095734,0.170994,0.000997,0.054497,0.477492,0.006272,0.016850,0.007447,0.006837,0.000426, and0.000898, respectively. Eight haplotypes were inferred based on-25385C>T, g.7635A>G, and g.8055C>T:CAC, CGT, TGT, TAC, CGC, TGC, CAT, and TAT. The population frequencies for these haplotypes were0.221,0.491,0.136,0.035,0.073,0.043,0.001and0.000, respectively.7) After SF treatment, AUC ratio and AUC_hyd of NR1I2-2413AA genotype were significantly reduced compared with AG and GG genotypes. NR1I2TGT carriers had significantly lower AUC ratio than that of TGT noncarriers, while the pharmacokinetic parameters of-24,020[GAGAAG>(-) variations did not displayed markedly difference.8) Regardless of the basic states or induction states, the metabolism activity of bupropion of complete mutation-type [CYP2B6*6/*6+NR1I2TGT+-24113AA+-24020(-)/(-)] always significantly showed lower metabolism activities compared with complete wild-type individuals.In conclusion, our studies provided mechanism to the individual differences in drug response of drug-drug interaction by SF administration with pharmacogeneties methods from molecular level, healthy subjects level and provided useful informations for the clinical combined use of SF and bupropion (CYP2B6substrate drugs). Before taking CYP2B6substrate drugs, patients were genotyped for CYP2B6, NR1I2, and POR would get better efficacy and little adverse reaction. |
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