Quercetin reduced the formation of N‐acetyl‐p‐benzoquinoneimine,a toxic metabolite of paracetamol in rats and isolated rat hepatocytes

N‐acetyl‐p‐benzoquinoneimine (NAPQI) is toxic metabolite of paracetamol formed primarily by cytochrome P4502E1 (CYP2E1) metabolic pathway when administered at therapeutic doses or overdose. The influence of quercetin (flavonoid) on the bioactivation of paracetamol to NAPQI was investigated using rat liver microsomes and rats in vivo. Paracetamol (80 mg/kg) was administered orally without or with silymarin (100 mg/kg), a known inhibitor of CYP2E1, CYP3A4 and quercetin (10 and 20 mg/kg) to rats for 15 consecutive days. Area under the plasma concentration–time curve (AUC_0‐∞) and the peakplasma concentration (C_max) of paracetamol were dose‐dependently increased with quercetin (10 and 20 mg/kg) compared to paracetamol control group (p < 0.001). On the other hand, the AUC_0‐∞ and C_max of NAPQI were decreased significantly with quercetin. The same results were observed with silymarin also. The elevated liver and kidney functional enzymes/compounds were significantly reduced by quercetin and silymarin compared to paracetamol control group. The formation of NAPQI was reduced in the incubation samples in presence of quercetin in experiment using isolated rat hepatocytes. The presentstudy results revealed that quercetin might be inhibited the CYP2E1‐mediated metabolism of paracetamol; thereby decreased the formation of NAPQI and protected the liver and kidney.     

Evaluation of the effect of quercetin treatment on CYP2C9 enzyme activity of diclofenac in healthy human volunteers

The purpose of present study was to evaluate the effect of quercetin on pharmacokinetics of diclofenac sodium (DIC) in healthy volunteers. The open‐label, 2 period, sequential study was conducted in 12 healthy volunteers. DIC 100 mg was administered during control and after quercetin phases. Quercetin 500 mg was administered twice daily for 10 days during quercetin phase. Treatment with quercetin significantly enhanced maximum plasma concentration (C_max)_, area under the curve (AUC_0‐∞), and half life, while significantly decreased elimination rate constant (k_el) and apparent oral clearance (CL/F) of DIC compared with control. On the other hand, C_max and AUC_0‐∞ of 4‐hydroxydiclofenac (4‐OHDIC) were decreased after quercetin treatment. In addition, geometric mean ratios and 90% confidence intervals for C_max and AUC_0‐∞ of DIC and 4‐OHDIC were both out of the no‐effect limits of 0.80–1.25, which indicates a significant pharmacokinetic interaction between quercetin and DIC. Furthermore, quercetin treatment significantly decreased metabolic ratios of C_max and AUC_0‐∞ suggesting that reduced formation of DIC to 4‐OHDIC. The results suggest that quercetin might have inhibited CYP2C9‐mediated metabolism of DIC. Accordingly, caution should be taken when quercetin is used in combination with therapeutic drugs metabolized by CYP2C9, and dose adjustment of CYP2C9 substrates may be necessary.     

粗叶悬钩子总生物碱对急性肝损伤大鼠肝组织CYP2E1与CYP3A1酶mRNA表达的影响

目的 研究粗叶悬钩子总生物碱对肝药物代谢酶CYP2E1和CYP3A1 mRNA表达的影响。     

黄药子与当归配伍对大鼠肝脏CYP1A2、CYP2E1基因mRNA表达的影响

目的：观察单用黄药子和黄药子配伍当归后对大鼠肝CYP1A2、CYP2E1基因mRNA表达的影响。方法：采用逆转录聚合酶链反应（RT-PCR）法测定大鼠肝CYP1A2、CYP2E1基因mRNA在给药后的变化。结果：黄药子组明显诱导CYP1A2、CYP2E1基因mRNA表达，黄药子配伍当归后mRNA表达受到抑制。结论：黄药子诱导P450酶系CYP1A2和CYP2E1mRNA的表达，导致肝中毒。当归配伍黄药子后抑制mRNA表达拮抗肝中毒。     

甲基莲心碱对大鼠肝CYP450酶含量及CYP2D1, CYP3A1,CYP2E1 mRNA的影响

目的 :探讨甲基莲心碱对大鼠微粒体混悬液蛋白中细胞色素P450(CYP450)含量,及其对CYP450亚型CYP3A1,CYP2D1,CYP2E1的mRNA表达水平的影响。 方法 :Wistar大鼠48只,随机分成空白组、肝药酶诱导剂组、肝药酶抑制剂组,甲基莲心碱(Nef)低、中、高剂量组。对照组给予1%羧甲基纤维素钠(CMC-Na),诱导剂组地塞米松100 mg ·kg^-1,抑制剂组酮康唑40 mg ·kg^-1,Nef低、中、高剂量组分别为Nef 10,20, 50 mg ·kg^-1 灌胃给药,1日1次,连续6 d。取大鼠的肝制备肝微粒体,测定肝微粒体中的蛋白浓度,用分光光度计对样品进行比色测定CYP450总酶的含量。并采用实时定量反转录——聚合酶链反应(Quantitive real-time RT-PCR)定量分析了大鼠CYP450亚型CYP3A1,CYP2D1,CYP2E1的mRNA表达水平。 结果 :甲基莲心碱在高剂量组的P450含量与空白组比较有显著性差异(P＜0.01),提示该药在较大剂量时(20~50 mg ·kg^-1)对CYP450有诱导作用。Nef在高剂量时,分别对CYP3A1和CYP2D1有诱导作用,可显著升高二者的活性(分别为空白组的1.92,2.99倍,P＜0.05);中剂量时对CYP2D1具有诱导作用(为空白组的2.40倍,P＜0.05);Nef在3个剂量下对CYP2E1均无诱导作用。 结论 :Nef在20,50 mg ·kg^-1剂量可增加CYP450总酶活性和CYP2D6 mRNA的表达,在50 mg ·kg^-1剂量可增加CYP3A1 mRNA的表达,提示Nef在较高剂量时可诱导肝药酶加速自身代谢。     

清开灵注射液对大鼠CYP1A2和2D6的影响

目的：通过清开灵注射液的大鼠体内、外实验,观察清开灵注射液对大鼠CYP1A2亚型,CYP2D6亚型的影响。方法：通过HPLC法测定全血中咖啡因的代谢率,观测清开灵注射液对大鼠CYP1A2活性的影响；通过HPLC法测定大鼠肝微粒体重组系统非那西丁的代谢比率,确定清开灵注射液对大鼠肝微粒体CYP1A2亚型的作用；测定大鼠肝微粒体重组系统右美沙芬的代谢比率,确定清开灵注射液对大鼠肝微粒体CYP2D6亚型的作用。结果：实验组中给予大鼠不同浓度的清开灵注射液(0.15,0.3,0.6 mL·kg^-1),其咖啡因代谢率为(15.9±3.8)%,(14.5±1.8)%,(12.3±1.2)%,对照组为(16.8±5.9)%,各剂量组及对照组间均无显著性差异；肝微粒体体外重组系统中,实验组各浓度清开灵注射液对CYP2D6没有影响；高剂量组清开灵注射液对CYP1A2有抑制作用。结论：清开灵注射液对CYP1A2和 CYP2D6的活性没有影响。     

Cocktail探针药物法评价百解胶囊对肝药酶亚型CYP2C19、CYP2E1的影响

目的:研究百解胶囊对大鼠肝药酶CYP2C19、CYP2E1活性的影响,探讨其解药物毒作用的机制。方法:将大鼠随机分为4组,即空白对照组、百解胶囊组(2.43g生药/kg)、百解胶囊组(0.27g生药/kg)、苯巴比妥钠组(10.8mg/kg),按上述剂量灌胃给药。以甲硝唑为内标,建立HPLC方法检测Cocktail探针药物奥美拉唑和氯唑沙宗在大鼠体内的代谢情况,评价百解胶囊对肝药酶CYP450的影响。结果:与空白对照组比较,百解胶囊组(2.43g生药/kg)对奥美拉唑的清除率(CL/F)明显增强,曲线下面积(AUC)明显减少,其半衰期(t1/2)亦有减少趋势;百解胶囊组(2.43g生药/kg)和百解胶囊组(0.27g生药/kg)对氯唑沙宗的清除率(CL/F)明显增强,曲线下面积(AUC)明显减少,半衰期(t1/2)明显缩短。结论:百解胶囊对大鼠肝药酶CYP2C19、CYP2E1具有诱导作用,可能是其解药物毒作用的机制之一。     

Therapeutic effects of curcumin on sepsis and mechanisms of action: A systematic review of preclinical studies

Sepsis is a complex disease that begins with an infectious disorder and causes excessive immune responses. Curcumin is considered as an active component of turmeric that can improve the condition in sepsis due to its anti‐inflammatory and antioxidant properties. PubMed, Embase, Google Scholar, Web of Science, and Scopus databases were searched. Searching was not limited to a specific publication period. Only English‐language original articles, which had examined the effect of curcumin on sepsis, were included. At first, 1,098 articles were totally found, and 209 articles were selected after excluding duplicated data; 46 articles were remained due to the curcumin effects on sepsis. These included 23 in vitro studies and 23 animal studies. Our results showed that curcumin and various analogs of curcumin can have an inhibitory effect on sepsis‐induced complications. Curcumin has the ability to inhibit the inflammatory, oxidative coagulation factors, and regulation of immune responses in sepsis. Despite the promising evidence of the therapeutic effects of curcumin on the sepsis complication, further studies seem necessary to investigate its effect and possible mechanisms of action in human studies.     

齐墩果酸对健康人体CYP1A2,CYP2E1及CYP3A4抑制作用的研究

 目的在人体内研究齐墩果酸对CYP1A2,CYP2E1及CYP3A4酶活性的影响,以预测齐墩果酸与常用临床药物的相互作用。方法分别以咖啡因、氯唑沙宗和咪哒唑仑作为CYP1A2,CYP2E1及CYP3A4的探药,采用随机、开放、双周期交叉设计,12名健康男性受试者在服用7d齐墩果酸前后均服用100mg咖啡因、400mg氯唑沙宗和7.5mg咪哒唑仑,服探药后采血测定探药及相应代谢产物的浓度,并计算相关参数。探药和代谢物的浓度分别用RP-HPLC和HPLC-MS测定。结果服用齐墩果酸7d后,咖啡因的代谢受到显著的抑制,其达峰时间、消除半衰期及药-时曲线下面积显著增加;氯唑沙宗的代谢受到轻微抑制,达峰浓度、达峰时间、消除半衰期及药-时曲线下面积均有升高趋势,但无显著性差异;咪哒唑仑的代谢未受影响。结论服用7d齐墩果酸对CYP1A2体内活性有显著抑制作用,对CYP2E1体内活性有轻微抑制作用,而对CYP3A4酶活性无影响。     

Effects of quercetin supplementation on glycemic control among patients with metabolic syndrome and related disorders: A systematic review and meta‐analysis of randomized controlled trials

This systematic review and meta‐analysis of randomized controlled trials was performed to determine the effect of quercetin supplementation on glycemic control among patients with metabolic syndrome and related disorders. Databases including PubMed, MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials were searched until August 30, 2018. Nine studies with 10 effect sizes out of 357 selected reports were identified eligible to be included in current meta‐analysis. The pooled findings indicated that quercetin supplementation did not affect fasting plasma glucose (FPG), homeostasis model of assessment‐estimated insulin resistance, and hemoglobin A1c levels. In subgroup analysis, quercetin supplementation significantly reduced FPG in studies with a duration of ≥8 weeks (weighted mean difference [WMD]: ?0.94; 95% confidence interval [CI; ?1.81, ?0.07]) and used quercetin in dosages of ≥500 mg/day (WMD: ?1.08; 95% CI [?2.08, ?0.07]). In addition, subgroup analysis revealed a significant reduction in insulin concentrations following supplementation with quercetin in studies that enrolled individuals aged <45 years (WMD: ?1.36; 95% CI [?1.76, ?0.97]) and that used quercetin in dosages of ≥500 mg/day (WMD: ?1.57; 95% CI [?1.98, ?1.16]). In summary, subgroup analysis based on duration of ≥8 weeks and used quercetin in dosages of ≥500 mg/day significantly reduced FPG levels.     

The antioxidant activity of artichoke (Cynara scolymus): A systematic review and meta‐analysis of animal studies

Current evidence has shown antioxidant activity of artichoke as a potent source of antioxidant compounds. However, it seems that the antioxidant activity of artichoke has not yet been reviewed. Therefore, the present study was designed to perform a systematic review of human studies, animal models, and in vitro systems and to conduct a meta‐analysis of animal studies on the antioxidant effects of artichoke. We searched four electronic databases till April 2018 using relevant keywords. All English language articles were assessed. For animal studies, standardized mean difference was pooled using a random effects model. The included studies were evaluated for eligibility and risk of bias. Thirty‐nine articles (two human, 23 animal, and 14 in vitro studies) were reviewed. The results of in vitro systems supported the antioxidant effect of artichoke, whereas limited clinical trials indicated no change or a slight improvement of antioxidant status. Finding of animal studies indicated that artichoke extract supplementation increased superoxide dismutase, catalase, glutathione, and glutathione peroxidase level in liver, as well as, decreased malondialdehyde level in liver and plasma of animals with induced disease significantly compared with comparison group. This meta‐analysis provided convincing evidence for antioxidant activity of artichoke in animals.     

中药对细胞色素P450 2E1影响的研究进展

细胞色素P450 2E1(CYP2E1)不仅参与药物代谢,还能催化许多前毒物和前致癌物的活化过程.近年发现许多中药能抑制或诱导CYP2E1活性,从而导致有益的和不利的药物相互作用.以近年国内外文献报道以及相关研究为依据,综述了中药有效成分、提取物和单复方对CYP2E1的影响,以及CYP2E1介导的中药药物相互作用,并对其影响机制进行简要介绍.以期为中药的临床合理使用,提高其有效性和安全性提供参考.     

乳香没药对细胞色素P450活性的影响

目的:考察乳香没药对细胞色素P450活性的影响。方法:56只小鼠分为对照组和乳香+没药3.15,2.10,1.05 g.kg-1剂量组,连续ig给药7 d;48只小鼠分为对照组和乳香、没药、乳香+没药组,ig给药3.15 g.kg-11次。所有小鼠末次药后30 min ip给予戊巴比妥钠,观察乳香没药对P450的影响。40只大鼠分为对照组、乳香组、没药组、乳香+没药组,以3.00 g.kg-1连续ig给药14 d,取肝脏制备各组动物肝微粒体,并用cocktail探针法考察乳香没药对大鼠CYP1A2,CYP2E1,CYP3A4的影响。结果:乳香+没药3.15,2.10,1.05 g.kg-1剂量连续给药7 d均可使戊巴比妥钠诱导的小鼠睡眠率降低(P<0.05,P<0.01),而单次给药3.15g.kg-1有使戊巴比妥钠诱导的小鼠睡眠率升高的趋势。乳香、没药及乳香+没药混合物组大鼠肝微粒体体外对非那西丁、氯唑沙宗代谢率显著高于对照组,而氨苯砜无明显差异。结论:乳香、没药连续用药均使CYP1A2,CYP2E1活性增强,而对CYP3A4则无显著影响。     

Effects of l-arginine supplementation on glycemic profile: Evidence from a systematic review and meta-analysis of clinical trials

BackgroundThe effects of l-arginine supplementation on indices of glycemic control and the role of many factors influencing this intervention have been controversial in clinical trials.ObjectiveThis meta-analysis was performed to assess the effects of l-arginine supplementation on indices of glycemic control, including fasting blood glucose (FBG), hemoglobin A1c (HbA1c), serum insulin and homeostatic model assessment of insulin resistance (HOMA-IR) levels in randomized controlled trials (RCTs).Search strategyThis study conducted a systematic review of RCTs published in PubMed, Scopus, Web of Science, Cochrane Library and Embase, up to 5 May, 2018.Inclusion criteriaStudies were included in this meta-analysis if they were RCTs with parallel design and reported sufficient data on participants before and after intervention, and outcomes of glycemic profile parameters in both the arginine supplementation and control groups.Data extraction and analysisThe screening of titles and abstracts was performed independently by two reviewers. Selected articles were considered if they met the study’s inclusion criteria. The quality of included studies was assessed by using the Cochrane Collaboration modified tool. From 710 articles retrieved in the initial search, only 10 trials were suitable for pooling the effects of arginine supplementation on serum glucose, insulin, HOMA-IR and HbA1c levels, with effect sizes of nine, eight, five and five, respectively.ResultsPooled random-effect analysis revealed that l-arginine supplementation could significantly decrease FBG level (weighted mean difference [WMD]: 3.35 mg/dL; 95% confidence interval [CI] = [−6.55, −0.16]; P = 0.04) and serum insulin level (WMD: −2.19 μIU/mL; 95% CI = [−3.70, −0.67]; P = 0.005). However, the effects of l-arginine supplementation on HOMA-IR and HbA1c were not significant. Results of subgroup analysis showed that supplementation with l-arginine could significantly decrease serum insulin levels when the dosage of l-arginine is > 6.5 g/d (WMD: −3.49 μIU/mL; 95% CI = [−5.59, −1.38]; P = 0.001), when the duration of supplementation is ≤ 12.8 weeks (WMD: −3.76; 95% CI = [−6.50, −0.98]; P = 0.008), when the participants are not diabetic patients (WMD: −2.54 μIU/mL; 95% CI = [−4.50, −0.50]; P = 0.01) and when the baseline serum level of insulin was > 20 μIU/mL (WMD: −3.98; 95% CI = [−6.31, −1.65]; P = 0.001).ConclusionAlthough the results of this study confirmed that supplementation with l-arginine could have significant effects on some glycemic profile indices of participants in clinical trials, the clinical importance of this reduction may not be meaningful.     

复方甘正浸膏对非酒精性脂肪性肝炎CYP2E1和PPARα表达的影响

目的观察复方甘正浸膏对高脂饮食建立的非酒精性脂肪性肝炎大鼠模型肝脏细胞色素P4502E1(CYP2E1)和过氧化物酶体增殖物激活受体(PPARα)表达的影响。方法大鼠随机分为正常组(不处理)、模型组、治疗组(予复方甘正浸膏),检测大鼠肝匀浆超氧化物歧化酶(SOD)活性、丙二醛(MDA)水平、甘油三酯(TG)含量及肝组织CYP2E1和PPARα的表达。结果模型组SOD活性较正常组明显降低,治疗组SOD活性较模型组显著增高,但仍低于正常;模型组MDA较正常组显著增高,治疗组MDA较模型组显著降低,但仍高于正常组;模型组TG含量明显高于正常组,治疗组与正常组无显著差异。模型组CYP2E1在肝组织中央静脉周围腺泡区肝细胞胞浆表达阳性率70%,正常组几乎无表达,治疗组阳性率20%,较模型组明显减少,与正常组相近。PPARα在正常组主要分布于肝组织汇管区周围肝细胞胞核内呈棕黄色表达,模型组较正常组表达细胞数明显减少,治疗组较模型组表达细胞数明显增多。结论复方甘正浸膏具有清除脂质过氧化和氧自由基的作用。     

探针药物法评价苦参对大鼠细胞色素P450 2E1代谢活性的影响

目的以氯唑沙宗作为探针药物,研究苦参对大鼠细胞色素P450 2E1(CYP 2E1)体内代谢活性的影响。方法将Wistar大鼠随机分为对照组、苦参组、苯巴比妥阳性对照组。苦参组大鼠ig给予苦参颗粒(100 mg/kg)溶液,对照组ig给予等体积的生理盐水,阳性对照组ip苯巴比妥注射液50 mg/kg,各组均每日给药1次,连续5 d。第6天各组大鼠尾iv氯唑沙宗(5 mg/kg)溶液,于给药前及给药后不同时间点眼内眦静脉取血0.8 mL,HPLC法测定氯唑沙宗血药浓度。结果与对照组相比,苦参组给予苦参5 d后,氯唑沙宗的AUC和Cmax明显降低(P<0.05、0.01),CL明显升高(P<0.05);而苦参组的主要药动学参数与苯巴比妥组比较无显著差异(P>0.05)。结论苦参可明显诱导大鼠CYP 2E1的体内代谢活性,其作用强度与苯巴比妥相当。     

Herb–drug interaction studies of herbs used in treatment of cardiovascular disorders—A narrative review of preclinical and clinical studies

About 70% of the world population is currently using medicinal herbs as complementary or alternative medicine, which is increasing at a tremendous pace in both developed and developing countries in the last two decades (World Health Organization Medicines Strategy 2002–2005). This increase in consumer demand of medicinal herbs continues despite the rarity of scientific data to establish their safety and efficacy profile. Its popularity is also attributed to several factors, including easy availability, cost effectiveness leading to better purchasing power and general perception that they are safe. Herbs are often administered concomitantly with therapeutic drugs for the treatment of major ailments, raising the potential for herb–drug interactions (HDIs). The major pathways postulated for HDIs involves the cytochrome P450 (CYP450)‐mediated inhibition or induction and transport and efflux proteins. In our review, we highlight frequently used herbal medicines for the treatment of cardiovascular disorders (CVD), their established HDIs studied using in vitro tools and in vivo pharmacokinetic and pharmacodynamic assays and case reports. Herbs have been divided into different sections on the basis of availability of HDI data in relevance to cardiovascular drugs: herbs reported to interact with cardiac drugs, herbs yet to be reported for interaction with drugs of any class and herbs reported to interact with drugs of other therapeutic category but not with cardiac drugs. The amount of active phytoconstituents present in the selected herbs and their extent of bioavailability are also mentioned. This review can serve as a quick reference database for physicians and health care professionals involved in CVD treatment, aimed at maximizing clinical outcomes with reduction in adverse and toxic effects.     

葛根散对急性酒精性肝损伤小鼠肝微粒体 CYP450含量及CYP2E1活性的影响

目的:考察经典解酒方葛根散对急性酒精性肝损伤小鼠肝微粒体细胞色素P450( CYP450)含量及细胞色素P450-2E1( CYP2E1)活性的影响.方法:实验小鼠分葛根散高、中、低剂量组、正常对照组和模型对照组,各给药组分别给予葛根散水煎剂(按生药量计,20,10,5 g·kg-1)ig,对照组代以等体积蒸馏水,每天1次,连续10 d;每天给药30 min后,模型对照组和各给药组以15 mL·kg-1 56％白酒ig,正常对照组代以等体积蒸馏水,以血清丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)及肝脏系数为参考指标,制备急性酒精性肝损伤小鼠模型;取小鼠肝组织检测葛根散对肝微粒体CYP450含量及CYP2E1活性的影响.结果:与正常对照组比较:模型对照组血清ALT、AST水平及肝脏系数显著升高(P＜0.01),肝微粒体蛋白含量无明显变化,CYP450含量及CYP2E1活性显著提高(P＜0.01).与模型对照组比较:葛根散各剂量组血清ALT,AST水平及大剂量组肝脏系数呈明显降低(P ＜0.05或P＜0.01),肝微粒体蛋白含量无明显变化,CYP450含量明显增多(P＜0.01)且有剂量差异性(P＜0.05),CYP2E1活性显著降低(P＜0.01)且有剂量差异性(P＜0.01).结论:葛根散对急性酒精性肝损伤小鼠肝功能具有良性干预作用,能提高酒精性肝损伤小鼠肝微粒体CYP450含量和降低CYP2E1活性.     

Curcumin-piperine co-supplementation and human health: A comprehensive review of preclinical and clinical studies

Curcumin is extracted from the rhizomes Curcuma longa L. It is known for its anti-inflammatory and anti-oxidant activities. Despite its safety and potential for use against various diseases, curcumin's utility is restricted due to its low oral bioavailability. Co-administration of curcumin along with piperine could potentially improve the bioavailability of curcumin. The present review aimed to provide an overview of the efficacy and safety of curcumin-piperine co-supplementation in human health. The findings of this comprehensive review show the beneficial effects of curcumin-piperine in improving glycemic indices, lipid profile and antioxidant status in diabetes, improving the inflammatory status caused by obesity and metabolic syndrome, reducing oxidative stress and depression in chronic stress and neurological disorders, also improving chronic respiratory diseases, asthma and COVID-19. Further high-quality clinical trial studies are needed to firmly establish the clinical efficacy of the curcumin-piperine supplement.