内皮抑素对不同生长期实体肿瘤的抑制效应

目的 探讨内皮抑素(ES)对小鼠不同生长期皮下肉瘤移植瘤的抑制作用.方法 随机将60只肉瘤荷瘤小鼠分为早期对照组(NS1)、早期ES组(V1)、中期对照组(NS2)和中期ES组(V2),每组15只.两ES组瘤体周围注射ES,1次/d,连续给药14 d;两对照组给于等量生理盐水.观察肿瘤生长情况,计算抑瘤率、微血管密度(MVD).结果 V1和V2组瘤体明显小于NSl和NS2组(P＜O.01或P(0.05),Vl组抑瘤率高于V2组(45.83% vs.30.54%)(P＜0.05);V1和V2组MVD明显低于NS1和NS2组(P＜0.01),V1组低于V2组(P＜0.05).结论 ES可显著地抑制肿瘤血管生成,从而抑制肿瘤的生长,早期用药效果比中期用药更好.     

DDAH/NOS途径参与甲基苯丙胺大鼠纹状体的神经毒性研究

目的 探讨二甲基精氨酸二甲基氨基水解酶(DDAH)/一氧化氮合酶(NOS)途径在甲基苯丙胺(METH)神经毒性中发挥的作用及其相关调控机制.方法 将20只♂ Wistar大鼠,随机分为NS对照组和METH组,分别ip生理盐水或METH 15mg·kg-1,bid,用药4 d.采用HE染色光镜观察大鼠脑组织的病理学改变,Western蛋白印迹法检测大鼠纹状体区的DDAH1蛋白表达水平,以紫外分光光度计检测NOS的活性.结果 METH组大鼠脑组织中出现神经元水肿和明显的噬神经细胞现象,与NS组相比,METH组大鼠纹状体区的DDAH 1蛋白表达水平显著性升高(P＜0.05),NOS的活性显著性升高(P＜0.01).结论 DDAH/NOS途径可能参与METH引起的大鼠纹状体区的神经损伤.     

地塞米松对罗哌卡因臂丛神经阻滞效果的影响

目的:评价地塞米松对罗哌卡因臂丛神经阻滞效果的影响。方法:45例择期或急症前臂及手部手术患者行腋路臂丛神经阻滞,ASAⅠ或Ⅱ级。随机分为3组,0.5%罗哌卡因30mL加地塞米松5mg(1mL),静脉注射生理盐水(NS)1mL(A组);0.5%罗哌卡因30mL加NS1mL,静脉注射地塞米松5mg(B组),0.5%罗哌卡因30mL加NS1mL,静脉注射NS1mL(C组)。结果:A组感觉、运动阻滞持续时间均长于B、C组(P<0.05),A组术后首次疼痛时间、镇痛持续时间明显长于B、C组(P<0.05),3组阻滞成功率为93%(14/15)、93%(14/15)和87%(13/15)。麻醉期间各组患者血流动力学均无明显改变。结论:地塞米松可以通过外周途径发挥镇痛作用,在0.5%罗哌卡因中加入5mg地塞米松可明显改善上肢手术臂丛神经阻滞效果,并可延长术后镇痛时间。     

人体对丙型肝炎病毒表位免疫应答的分析[英]

作者建立了肽酶免疫试验(PBEIA),以检测丙型肝炎病毒(HCV)感染早期的抗体应答.合成肽序列选自原型HCV基因组的核心区(HCV-C)、包膜区(PEP3、PEP4、NS1)和非结构区(NS2、NS3、NS4、NS5).同时收集了不同类型肝病病人(包括急慢性肝炎、肝硬化和肝细胞癌)、血液透析病人、肾移植术后病人和高危人群(如医务人员)的血清标本102份,分别用PBEIA和ELISA检测抗HCV抗体,用逆转录聚合酶链反应(RT-PCR)检测HCV RNA.     

参附注射液对大鼠小肠缺血-再灌注后肾损伤的影响

目的 观察参附注射液(SF)对大鼠小肠缺血-再灌注后肾结构、功能和肾组织中bcl-2、bax表达水平的影响. 方法将36只SD大鼠随机平分为假手术组 (C组),缺血-再灌注＋0.9%氯化钠溶液组(IR＋NS组),缺血-再灌注＋参附注射液预处理组(IR＋SF组),各12只. IR＋NS组和IR＋SF组夹闭大鼠肠系膜上动脉60 min后松开建立小肠缺血-再灌注模型,C组穿线但不结扎. C组和IR＋NS组分别于阻断前30 min用微量泵经股静脉恒速泵入0.9%氯化钠溶液10 mL&#8226;kg^-1,IR＋SF组同法泵入参附注射液10 mL&#8226;kg^-1. 光镜下观察肾组织结构,i-STAT自动分析仪检测血清尿素(Urea)及电解质含量,免疫组化方法检测肾组织中bcl-2、bax蛋白的表达,TUNEL法检测肾脏细胞的凋亡水平. 结果 光镜下可见IR＋NS组肾组织结构损伤较IR＋SF组严重. IR＋NS组血清Urea和 钾离子(K＋)水平分别为(15.88±1.38 )和(6.88±0.43)mmol&#8226;L^-1, C组分别为(5.82±0.39)和(4.28±0.24 ) mmol&#8226;L^-1,IR＋SF组分别为(8.03±0.77)和(5.03±0.31 )mmol&#8226;L^-1,IR＋NS组和IR＋SF组与C组比较,差异有统计学意义(P＜0.01),IR＋SF组较IR＋NS组显著降低(P＜0.01). IR＋NS组bcl-2和bax阳性细胞率分别为(0.242 5±0.036 5)%和(0.281 7±0.029 2)%,显著高于C组[分别为(0.013 7±0.008 6)%和(0.011 7± 0.009 4)%](P＜0.01), IR＋SF组分别为(0.176 3±0.030 2)%和(0.196 7±0.024 6)%,较IR＋NS组显著降低(P＜0.01). C组凋亡指数(apoptotic index,AI)为(0.014 2±0.009 0)%,IR＋NS组为(0.179 2±0.028 4)%,IR＋SF组为(0.124 2±0.026 4)%,IR＋NS组和IR＋SF组与C组比较,差异有统计学意义(P＜0.01),IR＋SF组较IR＋NS组显著降低(P＜0.01). 结论 参附注射液对小肠缺血-再灌注造成的肾损伤组织具有保护作用.     

P15~(INK4B)和P16~(INK4A)基因在鼻咽癌组织中异常甲基化

目的通过检测P15INK4B和P16INK4A基因启动子区甲基化情况,分析其与鼻咽癌发生发展及临床病理特征关系,探讨其可能在鼻咽癌临床早期分子生物学诊断和治疗中的作用。方法运用甲基化特异性聚合酶链反应(PCR)对54例鼻咽癌组织和20例正常鼻咽上皮组织的P15INK4B和P16INK4A基因启动子区甲基化状态进行检测。结果鼻咽癌组织中P15INK4B和P16INK4A基因启动子区甲基化阳性率分别为22%(12/54)和46%(25/54),二者总检出率为48%(26/54),26例甲基化的癌组织同时出现二者甲基化为11例;而在正常鼻咽上皮组织中未检测到P15INK4B和P16INK4A基因启动子区甲基化。结论P15INK4B和P16INK4A基因启动子区甲基化与患者临床病理特征无明显相关关系,为鼻咽癌早期事件,有望成为早期分子生物学诊断的标志物,将来还可能作为去甲基化基因治疗的靶点。二者在鼻咽癌发生发展中可能存在协同作用。     

83例重度妊高征临床分析

本文通过我院近10年救治重度妊高征83例的临床资料分析,重点探讨妊高征的治疗问题。临床资料　1987年11月至1996年11月本院产科住院分娩14462例,诊断重度妊高征83例,发生率为05%,其中先兆子痫29例,发生率02%,子痫14例,发生率01%。诊断标准按第三版全国高等院校统编教材。平均年龄295岁(20～39岁),其中<25岁24例,占289%,25～29岁36例(434%),30～34岁19例(229%),≥35岁4例(48%)。职业:工人、农民和无业者共55例(663%),干部28例(337%)。入院时孕周:<28周1例(12%),28～36周13例(157%),37～41周69例(831%)。初产妇77例,经产妇6例。双胎妊娠3例。…     

羟基喜树碱加超分割放射治疗Ⅲ期非小细胞肺癌的临床研究

目的探讨羟基喜树碱加同步胸部超分割放射治疗不能手术的期非小细胞肺癌(NSCLC)的临床疗效和毒副反应。方法1998年10月～2002年5月,采用羟基喜树碱(HCPT)加同步超分割放射治疗不能手术的Ⅲ期NSCLC病人29例。化疗为放射治疗开始的前5d和放射治疗结束的前5d,分别应用HCPT10mg NS250ml静点,每天1次,连用5天;胸部放射治疗方法为1.2GY/次,每天2次,总量为62.4～64.8GY/52～54次/36～38d。结果治疗结束后1个月评价近期疗效,有效率(CR PR)为86.2%(25/29),其中CR率为24.1%(8/29),PR率为62.1%(18/29),稳定10.3%(3/29),进展3.5%(1/29)。远期疗效1年生存率为74.1%,2年生存率为60%,3年生存率为49%。毒副反应放射性食道炎(RTOG/EORTG)度为17.2%(5/29),度为65.5%(19/29),度为13.8%(4/29),度为3.5%(1/29);白细胞下降(WHO)度为51.7%(15/29), Ⅱ度为6.9%(2/29);血小板下降(WHO)度为13.8%(4/29)。结论小剂量羟基喜树碱加同步超分割放射治疗不能手术的Ⅲ期NSCLC病人,疗效较好,毒副反应小,病人完全可以耐受,是一种切实有效的治疗方法。     

低分子量肝素治疗原发性肾病综合征疗效观察

肾病综合征(Nephrotic syndrome,NS)常处于高凝状态,易并发血栓形成.成年NS患者血栓形成发生率高达10%～40%[1],严重影响该病的治疗效果及预后,因此抗凝治疗是目前NS治疗的关键之一.我们对35例原发性NS患者,在常规治疗基础上加用低分子量肝素(LMWH,速避凝)治疗,与30例原发性NS患者单纯应用常规治疗对比,现将结果报告如下. 1 临床资料 1.1 病例选择:具有以下临床表现:(1)尿蛋白≥3.5g/24h;(2)血浆白蛋白≤30g/L ;(3)水肿;(4)血脂升高.其中(1)、(2)两条为诊断所必备,通过相关检查除外糖尿病肾病、狼疮性肾炎、紫癜性肾炎、乙肝病毒相关性肾炎及遗传性肾脏病等所致的继发性肾病综合征. 1.2 一般资料:本文65例为1998年1月至2001年1月住院的成年患者.其血小板、出凝血时间、血纤维蛋白原均在正常范围或高于正常范围.65例随机分成两组;观察组35例,其中男 20例,女15例;年龄14～63岁(平均29.2岁),13例行过肾活检.对照组30例,其中男18 例,女12例;年龄15～61岁(平均28.8岁),11例行过肾活检.两组在临床表现和病理类型方面具有可比性.     

多肽研究XIX:丙型肝炎病毒的免疫选择性

丙型肝炎病毒(HCV)基因组有显著的异源性和高度的可变性。其中E2HV(高变区)认为是宿主识别HCV,并且产生免疫压力的靶目标之一。文中设计并合成了三段多肽抗原P2,P9和P10。抗原性及免疫原性研究结果表明:(1)HCV宿主体内存在抗-E2HV抗体,但这种抗体是非中和性的,或者是抗体滴度太低。不足以中和HC病毒抗原;(2)同一基因型的HCV抗-E2HV抗体有某种共同的结构特点,从而使某一HCV病毒株E2HV抗原能够与其它病毒株抗-E2HV抗体反应,大约有30%的代表性;(3)丙型肝炎病毒E2HV区里碳端398～412多肽片段可以引起动物免疫应答。     

IN VIVO AND IN VITRO EFFECTS OF ATRIAL NATRIURETIC PEPTIDE ON RENIN RELEASE

1. This study investigated the effect of atrial natriuretic peptide on renin release from the kidney. The in vitro direct effect was examined in the animal experiment using renal cortical slices of rat, and the in vivo effect was observed in the human infusion study. 2. In the in vitro experiments, alpha-human atrial natriuretic peptide (alpha-hANP) ranging 10(-9) to 10(-6) mol/L did not change the basal renin release rate from the renal cortical slices (-9% at 10(-6) mol/L, NS). Isoproterenol (10(-6) mol/L) increased renin release by 40% (P < 0.001), whereas angiotensin II (10(-6) mol/L) suppressed it by 48% (P < 0.001). However, alpha-hANP did not affect the stimulative effect of isoproterenol or the inhibitory effect of angiotensin II. 3. Also in the human study, infusion of 25 ng/kg per min alpha-hANP failed to change the plasma renin activity in normotensive subjects (-4%) or patients with essential hypertension (+5%), or even in patients with raised renin levels such as renovascular hypertension (+10%) or congestive heart failure (-13%). 4. These results put forth negative views on the direct involvement of atrial natriuretic peptide in renin release from the juxtaglomerular apparatus.     

促性腺激素释放多肽(GRP)对体外培养小鼠垂体分泌LH的影响

合成的促性腺激素释放多肽(GRP)及其类似物GRp～NH₂,[Glu^7.9.14Lys^6.10]GRP(6～14),[phe¹⁴]GRP(5～14)和[phe¹⁴]GRP浓度在0.05mmol·L^-1时,具有刺激体外培养的小鼠垂体分泌LH的作用。其活性依此相当对照垂体的115.4,114.2,140,160和179%。小鼠于妊振第7～9天或第1～5天,每只sc[phe¹⁴]GRP1mg·d^-1,或于妊娠第2～4天每只sc[phe¹⁴]GRP(5～14)1mg·d^-1,有40～60%的妊娠动物出现死胎。     

Genetic polymorphisms of CYP2C9 and CYP2C19 in the Beninese and Belgian populations

AIMS: To investigate the distribution of cytochrome P450 2C9 (CYP2C9) and 2C19 (CYP2C19) genotype frequencies in the Beninese and Belgian Caucasian populations. METHODS: Beninese (n = 111) and Belgian (n = 121) were genotyped for CYP2C9*2, *3, *4, *5, and *11 as well as for CYP2C19*2 and*3. RESULTS: The distribution of alleles was: CYP2C9*1: 95.5 vs. 82.2% (P < 0.001); CYP2C9*2: 0 vs. 10% (P < 0.001); CYP2C9*3: 0 vs. 7.4% (P < 0.01); CYP2C9*4: both 0%; CYP2C9*5: 1.8 vs. 0% (P = 0.05); and CYP2C9*11: 2.7 vs. 0.4% (P < 0.05). The frequencies of the CYP2C19*2 allele were 13 vs. 9.1%, respectively. CYP2C19*3 was not detected in either population. The 95% confidence intervals for the differences of frequencies of CYP2C9*1, CYP2C9*2, CYP2C9*3, CYP2C9*4, CYP2C9*5, CYP2C9*11, CYP2C19*1, CYP2C19*2 and CYP2C19*3 between Belgian and Beninese were 7%, 19%; - 14%, - 6%; - 11%, - 4%; - 1%, 1%; 0%, 4%; 0%, 5%; - 10%, 2%; - 2%, 10%; - 1%; respectively. The distributions of CYP2C9 genotypes in the Beninese and Belgian individuals were: CYP2C9*1/*1: 91 vs. 67% (P < 0.00001); CYP2C9*1/*2: 0 vs. 18.2% (P < 0.0001); CYP2C9*1/*3: 0 vs. 11.6% (P < 0.001); CYP2C9*1/*5: 3.6 vs. 0% (P = 0.05); CYP2C9*1/*11: 5.4 vs. 0.8% (P = 0.05); CYP2C9*2/*3: 0 vs. 1.6% (NS); CYP2C9*3/*3: 0 vs. 0.8% (NS). The distributions of CYP2C19 genotypes between these ethnic groups were: CYP2C19*1/*1: 73.9 vs. 83.5% (NS); CYP2C19*1/*2: 26.1 vs. 14.9% (P < 0.05); CYP2C9*2/*2: 0 vs. 1.6% (NS). CONCLUSIONS: Differences of allele frequencies between Beninese and Belgian populations were statistically significant for CYP2C9*2, *3, *5 and *11, but not for CYP2C9*4 or for CYP2C19*2 and *3.     

RELAXANT EFFECTS OF BRAIN NATRIURETIC PEPTIDE ON GUINEA-PIG TRACHEAL SMOOTH MUSCLE

1. The relaxant effects of brain natriuretic peptide (BNP) were investigated on guinea-pig tracheal smooth muscle. 2. Various amounts of BNP (10^?9– 10^?6 mol/L) showed concentration-dependent relaxant effects on resting tone, leukotriene D₄ (LTD₄; 10^?8 mol/L) and endothelin-1 (ET-1; 10^?8 mol/L) induced contraction of tracheal smooth muscle with EC₅₀ values of 3.1± 0.7 ± 10^?8, 3.9 ± 1.0 ± 10^?8 and 3.5 ± 1.0 ± 10^?8 mol/L, respectively. 3. BNP increased tissue cyclic GMP levels in tracheal smooth muscle concentration dependently (187 ± 26 fmol/mg protein in control, 334 ± 77 fmol/mg protein at 10^?8 mol/L, 680 ± 54 fmol/mg protein at 10^?7 mol/L, 2162 ± 133 fmol/mg protein at 10^?6 mol/L). 4. With the addition of BNP, tissue cyclic GMP levels reached a maximum at 1–3 min. The relaxation of tracheal smooth muscle began at 1 min and reached a maximum level at 5 min after the superfusion of BNP (10^?6 mol/L). The elevation of cyclic GMP preceded the relaxation of tracheal smooth muscle. 5. These results suggest that BNP may have a potent relaxant effect on tracheal smooth muscle and this effect may be mediated by cyclic GMP level.     

人卵促性腺激素释放肽(hF-GRP)及其类似物合成和生物活性初探

用固相法合成了hF-GRP及其15个类似物。全部裂解均用三氟甲磺酸完成。产物总收率60%～80%。对所有合成肽进行了影响离体的小鼠垂体分泌LH^**的活性筛选。结果表明,当合成肽的浓度为0.05mmol/L时:(1)将hF-GRP的C端COOH变成CONH₂,活性变化不大;(2)C端残基Asn¹⁴被Phe替换后刺激垂体分泌LH的活性明显高于hF-GRP;(3)Thr³被Tyr替换后片段hF-GRP(3～13)有抑制LH分泌的活性;(4)其余类似物与空白对照相似。     

Lipid-lowering effects of TAK-475, a squalene synthase inhibitor,in animal models of familial hypercholesterolemia

The lipid-lowering effects of 1-[2-[(3R,5S)-1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-1,2,3,5-tetrahydro-2-oxo-5-(2,3-dimethoxyphenyl)-4,1-benzoxazepine-3-yl] acetyl] piperidin-4-acetic acid (TAK-475), a novel squalene synthase inhibitor, were examined in two models of familial hypercholesterolemia, low-density lipoprotein (LDL) receptor knockout mice and Watanabe heritable hyperlipidemic (WHHL) rabbits. Two weeks of treatment with TAK-475 in a diet admixture (0.02% and 0.07%; approximately 30 and 110 mg/kg/day, respectively) significantly lowered plasma non-high-density lipoprotein (HDL) cholesterol levels by 19% and 41%, respectively, in homozygous LDL receptor knockout mice. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, simvastatin and atorvastatin (in 0.02% and 0.07% admixtures), also reduced plasma levels of non-HDL cholesterol. In homozygous WHHL rabbits, 4 weeks of treatment with TAK-475 (0.27%; approximately 100 mg/kg/day) lowered plasma total cholesterol, triglyceride and phospholipid levels by 17%, 52% and 26%, respectively. In Triton WR-1339-treated rabbits, TAK-475 inhibited to the same extent the rate of secretion from the liver of the cholesterol, triglyceride and phospholipid components of very-low-density lipoprotein (VLDL). These results suggest that the lipid-lowering effects of TAK-475 in WHHL rabbits are based partially on the inhibition of secretion of VLDL from the liver. TAK-475 had no effect on plasma aspartate aminotransferase and alanine aminotransferase activities. Thus, the squalene synthase inhibitor TAK-475 revealed lipid-lowering effects in both LDL receptor knockout mice and WHHL rabbits.     

STUDIES OF PEPTIDE ANTIBIOTICS:

Tyrocidine A (TA) is an antibiotic cyclic decapeptide with the sequence of cyclo (-L-Val¹ -L-Orn²-L-Leu³-D-Phe⁴-L-Pro⁵-L-Phe⁶-D-Phe⁷-L-Asn⁸-L-Gln⁹-L-Tyr¹⁰-). Gramicidin S (GS) regarded as a homolog of TA is also a cyclic decapeptide with the sequence of cyclo (-L-Val¹-L-Orn²-L-Leu³-D-Phe⁴-L-Pro⁵- L-Val⁶-L-Orn⁷-L-Leu⁸ -D-Phe⁹ -L-Pro¹⁰ -). GS shows higher antibacterial activity, whereas TA exhibits inhibitory activity on the biosynthesis of RNA. Two analogs of TA, [L-Val⁶]-TA (12a) and [L-Orn⁷]-TA (12b), were synthesized by the conventional method in order to study the interrelationships between the two related antibiotics TA and GS. Antibacterial activities of 12a and TA are nearly the same, but the activity of 12b is significantly lower. The optical rotatory dispersion spectra of 12a, 12b, and TA showed a trough at 233 nm region; the troughs of 12a and TA are nearly the same in depth, but the trough of 12b is shallower. Relationships between structure and activity of 12a and 12b compared with TA and GS were discussed.     

胶束薄层色谱法同时测定APC片中3组分含量

应用胶束薄层色谱法同时测定复方乙酰水杨酸片 (APC)中的阿司匹林 (A)、非那西汀 (P)和咖啡因 (C)的含量。在聚酰胺薄膜上 ,以 2 %SDS 乙腈 NaAc Na2 HPO4 ·1 2H2 O(3∶1∶1 )为展开剂 ,测定波长为 2 73nm ,单波长反射法锯齿扫描 ,结果 ,点样量在 0 9～ 4 5 μg,A组分的点样量X(mi)与斑点积分面积的比值Y(Ai/As)呈良好的线性关系 ,其回归方程为 :Y =2 0 0 3 1X +0 81 5 9,r =0 9981 ,平均回收率为 1 0 1 3 % ,RSD 1 9% ;点样量在 0 6～ 3 0 μg,P组分的回归方程为 :Y =1 2 1 4 5X +0 4 1 0 6,r=0 9978,平均回收率为 99 2 % ,RSD 2 4 % ;点样量在 0 1 4～ 0 7μg,C组分的回归方程为 :Y =2 1 3 63X +0 64 5 2 ,r=0 9984 ,平均回收率为 :98 4 % ,RSD 3 1 %     

Age-related changes in two-pore domain acid-sensitive K⁺ channel expression in rat dorsal root ganglion neurons

1. Two‐pore domain K⁺ (K_2P) channel expression influences brain development. The K_2P channels, including two‐pore domain acid‐sensitive K⁺ (TASK) channels, contribute to the setting of the resting membrane potential of neurons. In addition to neurons in the brain, dorsal root ganglion (DRG) neurons also express K_2P channels. The aim of the present study was to identify postnatal changes in the expression of TASK channels in DRG neurons. 2. Expression of TASK channels (TASK‐1, TASK‐2 and TASK‐3) was compared between neonatal (postnatal Day (P) 1 or P2) and adult (P120) rat DRG using semiquantitative polymerase chain reaction, western blot analysis, immunostaining and the patch‐clamp technique. 3. In adult (P120) rat DRG, expression of TASK‐2 mRNA and protein was downregulated, whereas TASK‐3 mRNA and protein expression was upregulated. There were no consistent changes in TASK‐1 mRNA and protein expression. Single‐channel recordings showed very low TASK‐2‐ and TASK‐3‐like channel expression in P1–P2 DRG neurons (～10% in TASK‐2 and ～3% in TASK‐3). In P120 DRG, there was a reduction in the detection of TASK‐2‐like channels, whereas the detection of TASK‐3‐like channels increased. 4. These results show that TASK‐2 and TASK‐3 mRNA and protein expression undergoes age‐related changes in DRG neurons, indicating that TASK‐2 and TASK‐3 channels are likely to contribute to the setting of the resting membrane potential of DRG neurons in neonates and adults, separately or together, during DRG development.     

Interaction of buprenorphine and its metabolite norbuprenorphine with cytochromes p450 in vitro.

Buprenorphine is a thebaine derivative used in the treatment of heroin and other opiate addictions. In this study, the selective probe reactions for each of the major hepatic cytochromes P450 (P450s) were used to evaluate the effect of buprenorphine and its main metabolite norbuprenorphine on the activity of these P450s. The index reactions used were CYP1A2 (phenacetin O-deethylation), CYP2A6 (coumarin 7-hydroxylation), CYP2C9 (diclofenac 4'-hydroxylation), CYP2C19 (omeprazole 5-hydrxoylation), CYP2D6 (dextromethorphan O-demethylation), CYP2B6 (7-ethoxy-4-trifluoromethyl-coumarin 7-deethylation), CYP2E1 (chlorzoxazone 6-hydroxylation), and CYP3A4 (omeprazole sulfoxidation). Buprenorphine exhibited potent, competitive inhibition of CYP2D6 (Ki 10 +/- 2 microM and 1.8 +/- 0.2 microM) and CYP3A4 (Ki 40 +/- 1.6 microM and 19 +/- 1.2 microM) in microsomes from human liver and cDNA-expressing lymphoblasts, respectively. Compared with buprenorphine, norbuprenorphine demonstrated a lower inhibitory potency with CYP2D6 (22.4% inhibition at 20 microM norbuprenorphine) and CYP3A4 (13.6% inhibition at 20 microM) in microsomes from human cDNA-expressing lymphoblast cells. Furthermore, buprenorphine was shown to be a substrate of CYP2D6 (Km = 600 microM; Vmax = 0.40 nmol/min/mg protein) and CYP3A4 (Km = 36 microM; Vmax = 0.19 nmol/min/mg protein). The present in vitro study suggests that buprenorphine and its major metabolite norbuprenorphine are inhibitors of CYP2D6 and CYP3A4; however, at therapeutic concentrations they are not predicted to cause potentially clinically important drug interactions with other drugs metabolized by major hepatic P450s.