黄芪注射液对大鼠CYP2D代谢酶的影响

目的:探究黄芪注射液对大鼠CYP2D代谢活性的影响。方法:制备大鼠空白肝微粒体,加入黄芪注射液孵育,HPLC法测定代谢产物去甲右美沙芬的浓度,比较空白对照组和黄芪注射液低、中、高剂量组之间代谢产物浓度的差异,评价黄芪注射液对CYP2D活性的影响。结果:黄芪注射液低、中、高剂量组代谢产物的浓度与空白对照组相比,差异有统计学意义(P<0.05)。结论:黄芪注射液对大鼠CYP2D的活性有抑制作用。     

紫草羟基萘醌对大鼠肝微粒体CYP2D6的影响

目的研究紫草羟基萘醌（HNA）对大鼠肝微粒体CYP2D6的影响。方法 Wistar大鼠,♂,口服给予不同剂量的HNA（5,60 mg.kg-1.d-1）或等量的空白溶媒,连续给药2周后制备肝微粒体。以体外探针药物右美沙芬的代谢物右啡烷的生成速率来反映CYP2D6的活性,通过比较给药组与空白溶媒组酶活性的差异来评价HNA对大鼠肝微粒体CYP2D6的影响。结果建立了一种以右美沙芬为探针底物评价大鼠肝微粒体CYP2D6活性的方法。口服给予HNA两周后,两个剂量组大鼠的肝微粒体蛋白含量、细胞色素P450总量、b5含量以及CYP2D6的活性与空白溶媒组相比差异均无统计学意义。结论 5 mg.kg-1.d-1和60 mg.kg-1.d-1剂量的紫草羟基萘醌口服2周对Wistar大鼠肝微粒体CYP2D6的活性均无显著影响,没有明显的诱导或抑制作用。     

注射用丹参总酚酸(冻干)对人CYP450酶和P-糖蛋白体外抑制作用及对大鼠CYP1A2和CYP3A体内诱导作用(英文)

目的探讨注射用丹参总酚酸(冻干)(SLI)对人CYP450酶和P-糖蛋白体外抑制作用以及对大鼠CYP1A2和CYP3A体内诱导作用。方法①应用P450-GloTMCYP450检测试剂盒,通过化学发光法测定SLI和经典抑制剂对细胞色素P4501A2(CYP1A2),CYP2D6,CYP3A4,CYP2C19和CYP2C9的IC50值,通过比较SLI和经典抑制剂对相应细胞色素P450亚型的IC50值来判断SLI对人CYP450酶的体外抑制作用。②Wistar大鼠分别iv给予SLI 3,10和30 mg·kg-1和诱导剂苯巴比妥钠20 mg·kg-1,采用探针底物法,通过比较代谢产物的生成速率来评价SLI对大鼠CYP1A2和CYP3A的诱导作用。③应用ATP酶检测试剂盒,通过化学发光法测定ATP酶活性来评价SLI是否为P-gp的底物或抑制剂。结果①CYP1A2,CYP2C9,CYP2C19,CYP2D6和CYP3A4抑制剂的IC50与SLI对其的IC50进行比较(CYP1A2:0.12μmol·L-1vs 840μmol·L-1;CYP2C9:3.362μmol·L-1vs 704μmol·L-1;CYP2C19:3.236μmol·L-1vs 306μmol·L-1;CYP2D6:0.117μmol·L-1vs 2660μmol·L-1;CYP3A4:0.078μmol·L-1vs 1780μmol·L-1)。②与空白对照组(86.4±6.3)nmol·g-1.min-1相比,SLI 3,10和30 mg·kg-1组CYP1A2活性分别为83.4±6.6,82.5±4.0和(83.4±6.6)nmol·g-1.min-1。与空白对照组(16.1±0.9)nmol·g-1.min-1比较,SLI 3,10和30 mg·kg-1组CYP3A活性分别为15.7±0.6,15.9±0.7和(15.9±1.0)nmol·g-1.min-1,无显著性差异。③以临床血药浓度为依据设计的一系列浓度的SLI 0.0002,0.0006,0.002,0.006,0.017,0.052,0.156和0.468 g.L-1的ATP酶活性分别与空白对照组进行比较(5.8,5.3,5.8,5.5,5.8,5.2,,5.8,5.3,vs 5.75μmol·g-1.min-1),无显著性差异。结论SLI临床给药剂量既不能体外抑制人CYP1A2,CYP2D6,CYP3A4,CYP2C19和CYP2C9酶活性,也不能诱导大鼠CYP1A2和CYP3A,同时也不是P-gp的体外抑制剂或底物。     

Caspase抑制剂F1013对大鼠肝CYPs含量及其主要亚型mRNA表达的影响

目的:探讨Caspase抑制剂F1013对大鼠肝CYPs含量及其主要亚型CYP1A2,CYP2D1,CYP2E1,CYP2C11,CYP3A1 mRNA相对表达水平的影响。方法:Wistar大鼠40只,随机分成空白组、诱导剂组、F1013低、中、高剂量组。空白组和诱导剂组分别灌胃给予0.9%氯化钠溶液和地塞米松50 mg·kg-1.d-1,F1013低、中、高组分别肌内注射F1013 1.25,2.5,5.0 mg·kg-1.d-1,每日1次,连续6 d。取大鼠肝组织制备肝微粒体,测定微粒体蛋白浓度及CYP总酶含量。并采用实时定量荧光RT-PCR法分析大鼠CYP各主要亚型mRNA的相对表达水平。结果:F1013低、中、高组肝微粒体CYP总酶含量与空白组比有显著增高(P<0.05),提示该药对CYP总酶有诱导作用。低剂量组CYP2D1酶活性显著升高(为空白组2.54倍,P<0.05);中剂量组CYP1A2及CYP2E1酶活性显著升高,分别为空白组4.24和2.46倍(P<0.05);3个剂量的F1013对CYP2C11均无显著诱导作用。结论:F1013在1.25,2.5,5.0 mg.kg-1剂量范围内,可显著诱导CYP总酶活性。F1013 1.25 mg·kg-1可诱导CYP 2D1 mRNA表达,2.5 mg·kg-1剂量可诱导CYP1A2及CYP2E1 mRNA的表达,其诱导机制可能与升高各主要亚酶mRNA相对表达水平有关。     

盐酸小檗碱对大鼠肝微粒体细胞色素P450酶含量及活性的影响

目的考察盐酸小檗碱对大鼠肝微粒体的蛋白含量、CYP450酶总量和主要CYP450酶亚型(CYP1A2、CYP2D6、CYP3A4和CYP2C19)活性的影响。方法以溶剂为空白对照灌胃给予盐酸小檗碱250 mg/(kg·d),连续7 d,测定其肝微粒体蛋白含量、CYP450蛋白含量以及CYP1A2、CYP2D6、CYP3A4和CYP2C19活性。结果与空白对照组比较,盐酸小檗碱给药组大鼠肝微粒体蛋白含量及肝微粒体CYP450含量无明显差异(P>0.05)。盐酸小檗碱给药后,给药组大鼠的平均CYP3A4活性是空白对照组的1/2;而两组之间CYP1A2、CYP2D6和CYP2C19的活性相当。结论盐酸小檗碱对大鼠CYP3A4活性有一定抑制作用,对CYP1A2、CYP2D6和CYP2C19的活性没有影响。     

CYP1A2、CYP2D6和CYP2C19基因多态性与氯氮平及其代谢物血药浓度的相关性研究

目的：研究CYP1A2、CYP2D6和CYP2C19基因多态性与精神分裂症患者氯氮平（clozapine,CLZ）及其活性代谢物去甲氯氮平（N-desmethy clozapine,N-CLZ）血药浓度的相关性。方法：纳入156例经CLZ单药治疗1个月以上的精神分裂症患者,采集清晨服药前空腹血,采用液相色谱-串联质谱（LC-MS/MS）法测定CLZ及N-CLZ稳态谷浓度。通过Axiom基因芯片分析技术检测CYP1A2（*1C、*1F）、CYP2D6（*2、*10）、CYP2C19（*2、*3）等6个SNP位点的基因型,比较不同基因型患者CLZ及其代谢物的浓度剂量比（C/D）及代谢物与CLZ血药浓度比值（C_N-CLZ/C_CLZ）的差异。结果：CYP2D6*10基因多态性与N-CLZ C/D具有相关性（P<0.01）。CYP1A2*1C、CYP2D6（*2、*10）基因多态性与C_N-CLZ/C_CLZ具有相关性（P<0.05,P<0.01,P<0.01）。CYP1A2*1F、CYP2C19*2、CYP2C19*3基因多态性与C/D及C_N-CLZ/C_CLZ无相关性（P>0.05）。结论：CYP1A2*1C和CYP2D6（*2、*10）基因多态性对CLZ代谢存在影响,建议临床在使用CLZ治疗前检测患者CYP1A2*1C和CYP2D6（*2、*10）基因型,为CLZ个体化治疗提供参考。     

Cocktail探针药物法评价胃炎灵颗粒对大鼠体内CYP450活性的影响

目的研究胃炎灵颗粒对大鼠体内细胞色素P450酶活性的影响。方法分别以右美沙芬(CYP2D6)、咪达唑仑(CYP3A4)、奥美拉唑(CYP2C19)、茶碱(CYP1A2)、氯唑沙宗(CYP2E1)和甲苯磺丁脲(CYP2C9)作为探针底物,大鼠6只,每日灌胃胃炎灵颗粒4 g/kg,采用LC-MS/MS测定给药前后大鼠体内6种探针药物的血药浓度。结果胃炎灵颗粒连续给药10 d后,与给药前相比,大鼠体内的右美沙芬(P <0. 01)、甲苯磺丁脲(P <0. 01)代谢减慢,氯唑沙宗(P <0. 01)代谢加快,奥美拉唑、咪达唑仑、茶碱的代谢无显著差异。结论胃炎灵颗粒在大鼠体内对CYP2D6酶产生中强抑制作用,对CYP2C9酶产生弱抑制作用,对CYP2E1酶产生轻微诱导作用,对CYP3A4、CYP2C19和CYP1A2基本没有影响。     

冰片对大鼠体内CYP2D诱导作用研究

冰片是传统中药,近年来许多文献报道冰片能提高其他药物的生物利用度,促进其他药物进入血脑屏障,因而冰片与其他药物合用可能产生的药物相互作用受到高度重视,但冰片对肝脏细胞色素P450酶的影响却鲜有报道。本文研究了雄性Wistar大鼠连续灌胃冰片一周对大鼠肝脏CYP2D表达与活性以及对CYP2D探针底物右美沙芬大鼠体内药代动力学的影响。结果表明,冰片(33、100和300 mg·kg-1·d-1)给药一周对大鼠肝脏CYP2D1 m RNA和蛋白表达无明显影响,但却显著诱导了CYP2D活性(P<0.05),分别达到1.71、1.97和2.89倍。此外,与对照组相比,冰片(300 mg·kg-1·d-1)预给药一周组右美沙芬的达峰浓度Cmax降低了10.6%(P>0.05),曲线下面积AUC0-∞减少了27.5%(P<0.01),清除率CL/F增大了41.1%(P<0.01),表观分布容积Vz/F增大了23.1%(P>0.05),表明冰片预给药一周能明显加速CYP2D探针底物右美沙芬的体内清除。由于冰片对大鼠肝脏CYP2D活性的诱导作用,提示当冰片与CYP2D底物药物共用时,可能存在发生代谢性相互作用的风险。     

复方毛冬青颗粒对大鼠肝微粒体细胞色素P450酶的诱导作用研究

目的研究复方毛冬青颗粒对大鼠细胞色素P450酶的诱导作用。方法复方毛冬青颗粒0.5、2.0、6.0g·kg-1·d-13个剂量组,雄性SD大鼠连续灌胃7d,取肝脏组织,制备肝微粒体,应用"cocktail"方法检测CYP450酶活性的变化。结果复方毛冬青颗粒能明显的诱导大鼠肝脏CYP1A2和CYP2E1的活性,且呈剂量依赖性:0.5、2.0、6.0g·kg-1·d-13个剂量组同空白对照组比,使CYP1A2的活性分别增加了55.9%,93.4%,176.4%,使CYP2E1的活性分别增加了16.1%,60.4%,111.3%,而对其他亚型没有影响。结论丹参酮ⅡA对大鼠CYP1A2和CYP2E1亚型有诱导作用,提示可能导致药物相互作用。     

Cocktail探针药物法评价灯盏花素对大鼠CYP450体内代谢活性的影响

目的用Cocktail探针药物法研究灯盏花素对大鼠CYP1A2、CYP2C9、CYP2E1和CYP2D6体内代谢活性的影响。方法将大鼠随机分为3组,空白对照组、低剂量组和高剂量组。低剂量组和高剂量组分别尾静脉给予灯盏花素粉针剂1.8,5.4 mg.kg-1.d-1,空白对照组给予生理盐水,共14 d。各组分别于第15 d注射Cocktail探针溶液,用HPLC检测各探针药物的血药浓度,用DAS2.0计算药代动力学参数,评价相应的CYP450亚型的体内代谢活性。结果高剂量组美托洛尔的AUC和t1/2显著高于空白对照组,CL显著低于空白对照组(P<0.05)。低剂量组美托洛尔虽然也有相同趋势,但差异无统计学意义(P>0.05)。各组咖啡因、氯唑沙宗和甲苯磺丁脲的主要药代动力学参数均无显著差异(P>0.05)。结论高剂量灯盏花素粉针剂可明显抑制大鼠CYP2D6的体内代谢活性,而对CYP1A2、CYP2E1和CYP2C9无显著性影响。     

Amodiaquine, its desethylated metabolite, or both, inhibit the metabolism of debrisoquine (CYP2D6) and losartan (CYP2C9) in vivo

Objective To study the extent of in vivo inhibition by the antimalarial drug amodiaquine, its active metabolite N-desethylamodiaquine, or both, of the metabolism of four probe drugs of the enzymes CYP2D6, CYP2C19, CYP2C9 and CYP1A2.Methods Twelve healthy Swedish volunteers received a cocktail of four probe drugs (debrisoquine, omeprazole, losartan and caffeine) to determine their baseline metabolic capacities. After a washout period, they received a 600 mg oral dose of amodiaquine hydrochloride; and 2–3 h later the cocktail was administered again. One week after the intake of amodiaquine, the subjects received the cocktail a third time. The levels of probe drugs and their metabolites as well as amodiaquine and its metabolite were determined by HPLC.Results Plasma levels of amodiaquine and N-desethylamodiaquine could be followed in all subjects for 6 h and 28 days, respectively. Among the 12 subjects, a 3-fold variation in amodiaquine AUC and a 2-fold variation in N-desethylamodiaquine AUC, were observed. The CYP2D6 and CYP2C9 activities of the subjects were measured by debrisoquine and losartan phenotyping tests, respectively. There were significant mean increases in debrisoquine metabolic ratio (MR) between baseline and the second cocktail [MR_{2 h}−MR_baseline 1.426 (95% confidence interval 1.159, 1.755), P=0.002; ANOVA, Fisher LSD test] and in mean losartan MR between baseline and the second cocktail [MR_{2 h}−MR_baseline 1.724 (95% confidence interval 1.076, 2.762), P=0.026; ANOVA, Fisher LSD test]. The effects on CYP2D6 and CYP2C9 activities subsided within a week after intake of amodiaquine as tested by the phenotyping cocktail. The changes in omeprazole MRs and caffeine MRs were not statistically significant between any of the study phases.Conclusion A single dose of amodiaquine decreased CYP2D6 and CYP2C9 activities significantly compared to baseline values. Amodiaquine has the potential to cause drug-drug interactions and should be further investigated in malarial patients treated with drug combinations containing amodiaquine.     

CYP2D6联合CYP1A2基因多态性对老年晚期癌症伴发 抑郁状态患者奥氮平个体化用药的指导研究

目的：研究老年晚期癌症伴发抑郁状态患者细胞色素酶P450（Cytochrome P450,CYP）2D6联合CYP1A2基因多态性指导奥氮平（olanzapine,OLA）个体化用药。方法：选取2016年9月~2018年1月入院治疗的老年晚期癌症伴发抑郁状态患者80例,利用SPSS 23.0软件随机分为对照组20例和试验组60例,第1周对照组根据经验给予奥氮平初始剂量5 mg·d-1,试验组根据CYP2D6联合CYP1A2基因型给予不同初始剂量奥氮平（联合快代谢型为7.5 mg·d-1,中等代谢型为5 mg·d-1）。第2、3、4周根据奥氮平血药浓度、病情、不良反应调整剂量。给药后第1、4周末,比较两组血药浓度达标情况及疗效。结果：第1周末,试验组血药浓度、达到靶血药浓度范围患者比例、标准化血药浓度、HAMD-24减分率显著高于对照组[（14.13±3.95） vs. （9.59±3.83） ng·L-1,86.7% vs. 60.0%,（38.90±15.51） vs.（30.93±13.55） ng·mL-1·mg-1·kg-1,（28.17±6.52）% vs.（23.27±5.45）%,P<0.05],试验组4周调整剂量患者比例显著低于对照组（20.0% vs. 50.0%,P<0.05）。第1、4周末,试验组快代谢型与中等代谢型患者上述指标均无显著差异（P>0.05）。第1周末,试验组快代谢型患者血药浓度、达到靶血药浓度范围患者比例、标准化血药浓度、HAMD-24减分率显著高于对照组快代谢型[（15.13±3.61） ng·L-1 vs. （6.27±2.62） ng·L-1,86.9% vs. 14.3%,（32.53±11.45） ng·mL-1·mg-1·kg-1 vs. （19.27±8.00） ng·mL-1·mg-1·kg-1,（28.49±5.96）% vs. （21.01±5.44）%,P<0.05],试验组快代谢型4周调整剂量患者比例显著低于对照组快代谢型（17.4% vs. 100.0%,P<0.05）。结论：根据CYP2D6联合CYP1A2基因代谢型指导老年晚期癌症伴发抑郁状态患者服用奥氮平的初始剂量,能够更加有效地使各代谢型患者在治疗早期尽快达到有效奥氮平血药浓度。     

The influence of CYP2B6, CYP2C9 and CYP2D6 genotypes on the formation of the potent antioestrogen Z-4-hydroxy-tamoxifen in human liver

AIMS: To investigate in a large panel of 50 human liver samples the contribution of CYP2C9, CYP2D6, and CYP3A4 to the overall formation of the potent antioestrogen Z-4-hydroxy-tamoxifen, and how various genotypes affect its formation from tamoxifen. METHODS: The formation of Z-4-hydroxy-tamoxifen from 10 microm tamoxifen was studied in human liver microsomes (n=50), characterized for CYP2B6, CYP2C9, CYP2D6 and CYP3A4 expression, and CYP2B6, CYP2C9 and CYP2D6 genotype. The effect of chemical and monoclonal antibody inhibitors, and the formation in supersomes expressing recombinant CYP isoforms was also investigated. Z-4-hydroxy-tamoxifen was quantified using LC-MS analysis. RESULTS: Z-4-hydroxy-tamoxifen was formed by supersomes expressing CYP2B6, CYP2C9, CYP2C19 and CYP2D6, but not CYP3A4. In agreement with these data, the mean formation of Z-4-hydroxy-tamoxifen was inhibited 49% by sulphaphenazole (P=0.001), 38% by quinidine (P<0.05) and 13% by monoclonal antibody against CYP2B6 (MAB-2B6, P<0.05). Furthermore, Z-4-hydroxy-tamoxifen formation significantly correlated with both CYP2C9 expression (r(s)=0.256, P<0.05) and CYP2D6 expression (r(s)=0.309, P<0.05). Genotypes of CYP2D6, CYP2B6 and CYP2C9 had an effect on metabolite formation in such a way that samples with two nonfunctional CYP2D6, or two variant CYP2C9 or CYP2B6 alleles, showed lower enzyme activity compared with those with two functional or wild-type alleles, (5.0 vs 9.9 pmol mg(-1) protein min(-1), P=0.046, 5.1 vs 9.9 pmol mg(-1) protein min(-1), P=0.053, and 6.8 vs 9.4 pmol mg(-1) protein min(-1), P=0.054, respectively). CYP2D6 and CYP2C9 contribute on average 45 and 46%, respectively, to the overall formation of Z-4-hydroxy-tamoxifen. CONCLUSIONS: CYP2B6, CYP2C9 and CYP2D6 genotypes all affected Z-4-hydroxy-tamoxifen formation and can predict individual ability to catalyse this reaction.     

Involvement of CYP2C9 and UGT2B7 in the metabolism of zaltoprofen,a nonsteroidal anti-inflammatory drug,and its lack of clinically significant CYP inhibition potential

AIMS: To identify the cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) isoforms responsible for the formation of the primary metabolite(s) of zaltoprofen, and to predict possible drug interactions by investigating the inhibition of CYP isoforms in vitro. METHODS: The metabolism of zaltoprofen was studied in vitro using recombinant CYP and UGT isoform cDNA-expression systems. The effects of selective isoform inhibitors on zaltoprofen metabolism were studied using human liver microsomes. The inhibitory effects of zaltoprofen on the metabolism of selective probe substrates for CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 were also determined in human liver microsomes. RESULTS: Zaltoprofen was extensively metabolized by CYP2C9 and UGT2B7. CYP2C9 catalysed sulphoxidation but not hydroxylation of zaltoprofen. In the human liver microsomal metabolism study, zaltoprofen metabolism was markedly inhibited by sulphaphenazole, a selective inhibitor of CYP2C9. In the drug interaction study, negligible inhibition (< 15%) of the activities of CYP1A2, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 was apparent at 5 micro g ml(-1), the maximum plasma concentration observed in humans after oral administration of an 80 mg zaltoprofen tablet. However, zaltoprofen inhibited CYP2C9 by 26% at 5 micro g ml(-1). At higher concentrations, zaltoprofen produced some inhibition of CYP2C9 (IC50 = 19.2 micro g ml(-1); 64.4 micro m) and CYP3A4 (IC50 = 53.9 micro g ml(-1); 181 micro m). The free drug concentrations in plasma (0.02 micro g ml(-1), 67.0 nm) at the Cmax of the clinically effective doses are much lower than the IC50 values corrected for the nonspecific binding ratio of zaltoprofen to microsomal protein (15.5 micro g ml(-1) for CYP3A4, 49.5 micro g ml(-1) for CYP3A4). Furthermore, the maximum free drug concentrations in the hepatic intracellular was calculated to be 0.068 micro g ml(-1) and the increase in the AUC in the presence of zaltoprofen was estimated to be only 0.4% for CYP2C9 substrates and 0.1% for CYP3A4 substrates, respectively. CONCLUSIONS: Zaltoprofen is predominantly metabolized by CYP2C9 and UGT2B7, and is considered unlikely to cause significant drug interactions in vivo when coadministered with CYP substrates at clinically effective doses.     

Involvement of CYP1A2 in mexiletine metabolism

Aims Mexiletine has been reported to be hydroxylated by cytochrome P450 2D6 (CYP2D6) in humans. However, the involvement of CYP1A2 in the metabolism of mexiletine has been proposed based on the interaction with theophylline which is mainly metabolized by CYP1A2. The aim of this study was to clarify the role of human CYP1A2 in mexiletine metabolism.
Methods Human CYP isoforms involved in mexiletine metabolism were investigated using microsomes from human liver and B-lymphoblastoid cells expressing human CYPs. The contributions of CYP1A2 and CYP2D6 to mexiletine metabolism were estimated by the relative activity factor (RAF).
Results Mexiletine p - and 2-hydroxylase activities in human liver microsomes were inhibited by ethoxyresorufin and furafylline as well as quinidine. Mexiletine p - and 2-hydroxylase activities in microsomes from nine human livers correlated significantly with bufuralol 1'-hydroxylase activity ( r =0.907, P <0.001 and r =0.886, P <0.01, respectively). Microsomes of B-lymphoblastoid cells expressing human CYP1A2 exhibited lower mexiletine p - and 2-hydroxylase activities than those expressing human CYP2D6. It was estimated by RAF that the major isoform involved in mexiletine metabolism was CYP2D6, and the contribution of CYP1A2 to both mexiletine p - and 2-hydroxylase activities was 7–30% in human liver microsomes. However, the K _m values of the expressed CYP1A2 (∼15  μm ) were almost identical with those of the expressed CYP2D6 (∼22  μm ) and human liver microsomes.
Conclusions Mexiletine is a substrate of CYP1A2. The data obtained in this study suggest that the interaction of mexiletine with theophylline might be due to competitive inhibition of CYP1A2.     

淫羊藿总黄酮对大鼠肝微粒体CYP1A2、CYP3A4和CYP2E1活性的影响

评估淫羊藿总黄酮对大鼠肝细胞色素P450及其主要亚型活性的潜在影响。淫羊藿总黄酮以300mg／kg／d的剂量对SD大鼠进行连续灌胃处理15天，测定肝微粒体中cYP450含量与CYP1A2、CYP3A4和CYP2E1亚型活性，观察淫羊藿总黄酮的效应。CYP1A2的活性用荧光比色法进行测定，CYP3A4和CYP2E1的活性用紫外可见分光光度法测定。淫羊藿总黄酮处理后的大鼠肝脏CYP450含量及CYP1A2、CYP3A4和CYP2E1亚型活性均明显增高，其中CYP1A2和CYP2E1活性升高显著（P〈0．01）。淫羊藿总黄酮对大鼠肝脏CYP450及主要亚型CYP1A2、CYP3A4和CYP2E1活性均有诱导效应。     

The human hepatic metabolism of simvastatin hydroxy acid is mediated primarily by CYP3A,and not CYP2D6

AIMS: To identify the cytochrome P450 (CYP) isoforms responsible for the metabolism of simvastatin hydroxy acid (SVA), the most potent metabolite of simvastatin (SV). METHODS: The metabolism of SVA was characterized in vitro using human liver microsomes and recombinant CYPs. The effects of selective chemical inhibitors and CYP antibodies on SVA metabolism were assessed in human liver microsomes. RESULTS: In human liver microsomes, SVA underwent oxidative metabolism to three major oxidative products, with values for Km and Vmax ranging from about 50 to 80 microM and 0.6 to 1.9 nmol x min(-1) x mg(-1) protein, respectively. Recombinant CYP3A4, CYP3A5 and CYP2C8 all catalysed the formation of the three SVA metabolites, but CYP3A4 was the most active. CYP2D6 as well as CYP2C19, CYP2C9, CYP2A6, CYP1A2 did not metabolize SVA. Whereas inhibitors that are selective for CYP2D6, CYP2C9 or CYP1A2 did not significantly inhibit the oxidative metabolism of SVA, the CYP3A4/5 inhibitor troleandomycin markedly (about 90%) inhibited SVA metabolism. Quercetin, a known inhibitor of CYP2C8, inhibited the microsomal formation of SVA metabolites by about 25-30%. Immunoinhibition studies revealed 80-95% inhibition by anti-CYP3A antibody, less than 20% inhibition by anti-CYP2C19 antibody, which cross-reacted with CYP2C8 and CYP2C9, and no inhibition by anti-CYP2D6 antibody. CONCLUSIONS: The metabolism of SVA in human liver microsomes is catalysed primarily (> or = 80%) by CYP3A4/5, with a minor contribution (< or = 20%) from CYP2C8. CYP2D6 and other major CYP isoforms are not involved in the hepatic metabolism of SVA.     

慢性间断性低氧对大鼠肝脏CYP3A_2和CYP2E_1的影响研究

目的研究慢性间断性低氧对大鼠肝脏CYP3A2和CYP2E1的影响。方法将大鼠随机分为对照组、低氧3d组、低氧7d组、低氧14d组、低氧28d组,低氧处理结束24h后,常规腹腔注射麻醉,摘取眼球血液2ml制备血清,并测定丙氨酸氨基转移酶(ALT)、天门冬酸氨基转移酶(AST)、红霉素N-脱甲基酶(ERD)、苯胺羟化酶(ANH)活性;取新鲜肝组织以制备微粒体和提取核糖核酸(RNA),并以RT-PCR进行基因片段扩增以检测大鼠肝脏细胞色素CYP3A2、CYP2E1的mRNA表达水平。结果慢性间断性低氧对血清ALT、AST活性无明显影响;低氧7d后,大鼠肝脏ERD、ANH活性明显升高,28d时诱导率分别为155.5%、42.2%;同时,CYP3A2、CYP2E1mRNA的表达水平也分别增加了220.5%、102.8%。结论慢性间断性低氧能显著增加大鼠肝脏ERD、ANH活性,其机制可能与其在转录水平上提高肝脏CYP3A2和CYP2E1的基因表达水平有关。