OBJECTIVE: To compare the accuracy of five warfarin-dosing algorithms and warfarin stable dose model (2.5 mg/day) for Shandong population. METHODS: One hundred and twenty five patients who achieved stable warfarin dose were enrolled. Clinical and genetic data were used to evaluate the value of each algorithm by calculating the percentage of patients whose predicted warfarin dose was within 20% of the actual stable therapeutic dose and mean absolute error (MAE). RESULTS: The frequency of patients with CYP2C9*1/*1, CYP2C9*1/*3 and CYP2C9*1/*2 genotype was 92.00%, 7.20%, 0.80%, respectively. That of VKORC1-1639 AA, AG and GG genotype was 82.40%, 15.20%, 2.40%, respectively. CYP4F2*1/*1, *1/*3, *3/*3 genotype was 50.40%, 39.20%, 10.40%, respectively. With the same genotypes for other loci, patients who carried at least one VKORC1-16398G mutant allele had increased warfarin stable daily dose compared with VKORC1-1639AA. Compared with CYP4F2*1/*1, those carrying at least one CYP4F2*3 mutant allele had warfarin stable daily dose increased by 5.9%-13.00%. The percentage of ideal prediction calculated from IWPC model (59.20%), Huang model (57.60%) and Ohno model (52.80%) were higher than others. The MAE were 0.35 (95%CI: 0.11-0.49), 0.15 (95%CI: 0.10-0.32), 0.39 (95%CI: 0.12-0.51), respectively. CONCLUSION The polymorphisms of CYP2C9, VKORC1 and CYP4F2 genes can influence the stable dose of warfarin in Shandong population. IWPC algorithm is suitable for guiding the use of warfarin in this population.
Anticoagulants ; administration & dosage ; Aryl Hydrocarbon Hydroxylases ; Cytochrome P-450 CYP2C9 ; genetics ; Cytochrome P450 Family 4 ; genetics ; Dose-Response Relationship, Drug ; Genotype ; Humans ; Models, Theoretical ; Polymorphism, Genetic ; Vitamin K Epoxide Reductases ; genetics ; Warfarin ; administration & dosage

The fields of pharmacogenetics and pharmacogenomics have become increasingly promising regarding the clinical application of genetic data to aid in prevention of adverse reactions. Specific screening tests can predict which animals express modified proteins or genetic sequences responsible for adverse effects associated with a drug. Among the genetic variations that have been investigated in dogs, the multidrug resistance gene (MDR) is the best studied. However, other genes such as CYP1A2 and CYP2B11 control the protein syntheses involved in the metabolism of many drugs. In the present study, the MDR-1, CYP1A2 and CYP2B11 genes were examined to identify SNP polymorphisms associated with these genes in the following four canine breeds: Uruguayan Cimarron, Border Collie, Labrador Retriever and German Shepherd. The results revealed that several SNPs of the CYP1A2 and CYP2B11 genes are potential targets for drug sensitivity investigations.
Animals ; Aryl Hydrocarbon Hydroxylases/*genetics/metabolism ; Cytochrome P-450 CYP1A2/*genetics/metabolism ; Dogs/*genetics/metabolism ; P-Glycoprotein/*genetics/metabolism ; *Polymorphism, Single Nucleotide ; Steroid Hydroxylases/*genetics/metabolism

The aim of the present study is to investigate how cytochrome P450 enzymes (CYP) 2C8-derived epoxyeicosatrienoic acids (EETs) regulate the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway and protect against oxidative stress-induced endothelial injuries in the development and progression of atherosclerosis. In this study, cultured human umbilical vein endothelial cells (HUVECs) were transfected with CYP2C8 or pretreated with exogenous EETs (1 μmol/L) before TNF-α (20 ng/mL) stimulation. Apoptosis and intracellular ROS production were determined by flow cytometry. The expression levels of ROS-associated NAD(P)H subunits gp91 and p47, the anti-oxidative enzyme catalase (CAT), Nrf2, heme oxygenase-1 (HO-1) and endothelial nitric oxide synthase (eNOS) were detected by Western blotting. The results showed that CYP2C8-derived EETs decreased apoptosis of HUVECs treated with TNF-α. Pretreatment with 11, 12-EET also significantly blocked TNF-α-induced ROS production. In addition, 11, 12-EET decreased oxidative stress-induced apoptosis. Furthermore, the ability of 11, 12-EET to protect cells against TNF-α-induced apoptosis via oxidative stress was abrogated by transient transfection with Nrf2-specific small interfering RNA (siRNA). In conclusion, CYP2C8-derived EETs prevented TNF-α-induced HUVECs apoptosis via inhibition of oxidative stress associated with the Nrf2 signaling.
8,11,14-Eicosatrienoic Acid ; analogs & derivatives ; metabolism ; pharmacology ; Adaptor Proteins, Signal Transducing ; genetics ; metabolism ; Apoptosis ; drug effects ; Aryl Hydrocarbon Hydroxylases ; genetics ; metabolism ; Atherosclerosis ; genetics ; metabolism ; pathology ; Catalase ; genetics ; metabolism ; Cytochrome P-450 CYP2C8 ; genetics ; metabolism ; Gene Expression Regulation ; Heme Oxygenase-1 ; genetics ; metabolism ; Human Umbilical Vein Endothelial Cells ; cytology ; drug effects ; metabolism ; Humans ; Membrane Glycoproteins ; genetics ; metabolism ; Models, Biological ; NADPH Oxidase 2 ; NADPH Oxidases ; genetics ; metabolism ; NF-E2-Related Factor 2 ; antagonists & inhibitors ; genetics ; metabolism ; Nitric Oxide Synthase Type III ; genetics ; metabolism ; RNA, Small Interfering ; genetics ; metabolism ; Reactive Oxygen Species ; antagonists & inhibitors ; metabolism ; Signal Transduction ; Tumor Necrosis Factor-alpha ; metabolism ; pharmacology

OBJECTIVETo assess the association of cytochrome P450 gene single nucleotide polymorphisms (SNPs) with susceptibility to gout in ethnic Han males from coastal regions of Shandong province.

METHODSFour hundred and eighty male patients with gout and 480 healthy male controls were included. Genotyping was carried out with a custom Illumina GoldenGate Genotyping assay to detect SNP rs2275620 of CYP2C8 gene, SNP rs2070676 of CYP2E1 gene, SNP rs837395 of CYP4B1 gene, and SNP rs194150 of TBXAS1 gene. The association was assessed with chi-square test.

RESULTSNo significant difference has been found between the two groups in regard to the genotypic and allelic frequencies of the TT, AT, AA genotypes and A, T alleles of the SNP rs2275620 of the CYP2C8 gene (P=0.88; P=0.97), the CC, CG, GG genotypes and C,G alleles of SNP rs2070676 of the CYP2E1 gene (P=0.24; P=0.09), the TT, AT, AA genotypes and A, T alleles of SNP rs837395 of the CYP4B1 (P=0.88; P=0.97), and TT, AT, AA genotypes and the A,T alleles of SNP rs194150 of TBXAS1 gene (P=0.15; P=0.06).

CONCLUSIONThis study has identified no association of SNP loci rs2275620(A/T) of CYP2C8, rs2070676(C/G) of CYP2E1, rs837395(A/T) of CYP4B1 and rs194150(A/T) of TBXAS1 with gout in ethnic Han males from coastal regions in Shandong province. However, our result needs to be replicated in larger sets of patients collected from other regions and populations.

Adult ; Aryl Hydrocarbon Hydroxylases ; genetics ; Asian Continental Ancestry Group ; ethnology ; genetics ; China ; ethnology ; Cytochrome P-450 CYP2C8 ; genetics ; Cytochrome P-450 CYP2E1 ; genetics ; Disease Susceptibility ; Female ; Gout ; enzymology ; ethnology ; genetics ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Thromboxane-A Synthase ; genetics

The prevalence of Helicobacter pylori infection in Korea shows a decreasing trend and has changed to that of developed country, especially for those below 30 years old. However, the primary antibiotic resistance rates are higher than those of developed countries. The reason for the decrease in the efficacy of standard triple therapy is mainly due to the increase in the resistance against clarithromycin. Sequential therapy seems to be more effective than the standard triple therapy, but the intention-to-treat eradication rate of sequential therapy in Korea, which is mostly under 80.0%, is still not satisfactory. Therefore, a promising regimen is needed. Recently, the Japanese health insurance system admitted 'H. pylori-infected gastritis' as an indication of eradication. Furthermore, the Kyoto Consensus Meeting on H. pylori Gastritis held from January 30th to February 1st, 2014, proposed that 'all H. pylori positive patients should be offered to receive H. pylori eradication'. This suggests that the concept of eradication has been changed from 'treatment' to 'prevention'. Various individualized tailored therapy based on the polymorphism, age and other demographic factors and antibiotic resistance has been attempted to maximize H. pylori eradication therapy. The aim of this article is to review the current epidemiology, H. pylori resistance state, treatment guideline, and to assess the possible future strategy and treatment for H. pylori infection in Korea.
Anti-Bacterial Agents/pharmacology/*therapeutic use ; Aryl Hydrocarbon Hydroxylases/genetics/metabolism ; Clarithromycin/pharmacology/therapeutic use ; Disease Eradication/trends ; Drug Resistance, Bacterial ; Drug Therapy, Combination ; Guidelines as Topic ; Helicobacter Infections/*drug therapy/epidemiology ; *Helicobacter pylori/drug effects ; Humans ; Quinolones/pharmacology/therapeutic use ; Republic of Korea ; Treatment Failure

OBJECTIVETo evaluate the effect of VKORC1, CYP2C9, GGCX, PROC, EPHX1 and CYP4F2 gene polymorphisms on Warfarin maintenance dose variation in Chinese Han Population.

METHODSFour hundred eighty-eight patients with prosthetic heart valves, atrial fibrillation or pulmonary thromboembolism and achieved stable Warfarin dose were enrolled. TaqMan probe or direct sequencing were used to genotype Y9VKORC1, CYP2C9, GGCX, EPHX1 and CYP4F2 gene polymorphisms. Demographic characteristics, stable therapeutic dose of Warfarin and concomitant medications were collected for all patients. The effect of VKORC1, CYP2C9, GGCX, PROC, EPHX1 and CYP4F2 gene polymorphisms, demographic characteristics and concomitant medications on Warfarin daily maintenance dose were analyzed with statistical method.

RESULTSVKORC1 and CYP2C9 gene polymorphisms could explain more than 50% Warfarin maintenance dose variation in recruited patients, while CYP4F2 gene polymorphisms could only explain 1%. GGCX, PROC and EPHX1 gene polymorphisms had no impact no Warfarin maintenance dose. VKORC1 and CYP2C9 gene polymorphisms have a greater impact on Warfarin maintenance dose compared with demographic characteristics and concomitant medications.

CONCLUSIONVKORC1 and CYP2C9 gene polymorphisms have a significant impact on Warfarin maintenance dose in Chinese Han population.

Adult ; Aged ; Aryl Hydrocarbon Hydroxylases ; genetics ; Asian Continental Ancestry Group ; ethnology ; genetics ; Atrial Fibrillation ; drug therapy ; ethnology ; genetics ; Cytochrome P-450 CYP2C9 ; Cytochrome P-450 Enzyme System ; genetics ; Cytochrome P450 Family 4 ; Dose-Response Relationship, Drug ; Epoxide Hydrolases ; genetics ; Female ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Protein C ; genetics ; Pulmonary Embolism ; drug therapy ; ethnology ; genetics ; Treatment Outcome ; Vitamin K Epoxide Reductases ; genetics ; Warfarin ; administration & dosage ; Young Adult

Anticonvulsants ; adverse effects ; Aryl Hydrocarbon Hydroxylases ; genetics ; Asian Continental Ancestry Group ; genetics ; Camptothecin ; analogs & derivatives ; metabolism ; Carbamazepine ; adverse effects ; Cytochrome P-450 CYP2C19 ; Glucuronosyltransferase ; genetics ; HLA-A Antigens ; genetics ; HLA-B Antigens ; genetics ; Humans ; Platelet Aggregation Inhibitors ; metabolism ; Stevens-Johnson Syndrome ; genetics ; Ticlopidine ; analogs & derivatives ; metabolism ; Topoisomerase I Inhibitors ; metabolism

Triptolide (TP) is a major active component in Tripterygium root, but its therapeutic window was very narrow due to its severe multi-organ toxicity. In this work, the effect of TP combined with glycyrrhetic acid (GA) on mRNA expression and activity of four cytochrome P450 (CYP) enzymes in rat liver was studied after intragastric administration of TP (0.05, 0.3 and 0.6 mg x kg(-1) x day(-1)) and TP (0.6 mg x kg(-1) x day(-1)) combined with GA (30 mg x kg(-1) x day(-1)) for 7 consecutive days. Compared with the control, the high dose of TP significantly up-regulated the mRNA expression levels of CYP2E1, 1A2, 3A1 and 2C11, the co-administration of TP and GA further up-regulated the mRNA expression levels of CYP3A1, 2C11 and 2E1 as compared with the high dose of TP. Meanwhile, TP at high dose and combined with GA significantly increased CYP3A-associated testosterone 6beta-hydroxylation activity (2.2-fold and 4.1-fold, respectively) as compared with the control. Because TP is mainly metabolized by CYP3A2 in male rats, the present work indicated that TP-induced increase of CYP3A activity might be an important reason for the rapidly metabolic clearance of TP in rat liver, and GA can reduce the hepatotoxicity of TP by promoting its hepatic metabolic clearance. Furthermore, the results also suggest that the drug interactions might be occurred when TP and GA were co-administered with other CYP3A substrate drug.
Animals ; Aryl Hydrocarbon Hydroxylases ; genetics ; metabolism ; Cytochrome P-450 CYP1A2 ; genetics ; metabolism ; Cytochrome P-450 CYP2E1 ; genetics ; metabolism ; Cytochrome P-450 CYP3A ; genetics ; metabolism ; Cytochrome P-450 Enzyme System ; genetics ; metabolism ; Cytochrome P450 Family 2 ; Diterpenes ; administration & dosage ; isolation & purification ; pharmacology ; Dose-Response Relationship, Drug ; Drug Combinations ; Drug Interactions ; Enzyme Activation ; Epoxy Compounds ; administration & dosage ; isolation & purification ; pharmacology ; Glycyrrhetinic Acid ; isolation & purification ; pharmacology ; Liver ; enzymology ; Male ; Phenanthrenes ; administration & dosage ; isolation & purification ; pharmacology ; Plant Roots ; chemistry ; Plants, Medicinal ; chemistry ; RNA, Messenger ; metabolism ; Rats ; Rats, Wistar ; Steroid 16-alpha-Hydroxylase ; genetics ; metabolism ; Tripterygium ; chemistry

The paper is to report the study of the effect of Shenfu injection on the enzyme activity of liver CYP450 and its mRNA level of rat liver. Microsome of rat liver was prepared after intravenous administration of Shenfu injection for 7 days. The enzyme activity was quantified by Cocktail method. Meanwhile, the mRNA expression of CYP1A2, CYP2B1/2, CYP2C11 and CYP3A1 in the liver was detected by RT-PCR. Shenfu injection obviously induced the enzyme activities of CYP2B and CYP2C. Meantime Shenfu injection decreased the enzyme activities of CYP1A2 and CYP3A. The mRNA levels of CYP2B and CYP2C were also induced in rats treated with Shenfu injection. But it obviously inhibited the mRNA level of CYP1A2 and CYP3A. Since the enzyme activity and mRNA level were obviously changed after administration, the potential effect of drug-drug interaction should be concerned.
Aconitum ; chemistry ; Animals ; Aryl Hydrocarbon Hydroxylases ; genetics ; metabolism ; Cytochrome P-450 CYP1A2 ; genetics ; metabolism ; Cytochrome P-450 CYP2B1 ; genetics ; metabolism ; Cytochrome P-450 CYP3A ; genetics ; metabolism ; Cytochrome P-450 Enzyme System ; genetics ; metabolism ; Cytochrome P450 Family 2 ; Drug Combinations ; Drugs, Chinese Herbal ; administration & dosage ; isolation & purification ; pharmacology ; Injections ; Male ; Microsomes, Liver ; enzymology ; Panax ; chemistry ; Plants, Medicinal ; chemistry ; RNA, Messenger ; metabolism ; Rats ; Rats, Sprague-Dawley ; Steroid 16-alpha-Hydroxylase ; genetics ; metabolism

This paper is to report the development of a high-throughput in vitro system to screen hPXR/CAR mediated CYP2B6 drug inducers, and the application of it into the quick determination of induction activity toward CYP2B6 by various commonly used traditional Chinese medicines (TCMs) extract. Dual reporter gene assays were performed. The hPXR/CAR expression vectors and the reporter vector pGL3-CYP2B6-Luc involved in the distal and proximal promoters of CYP2B6 were co-transfected into HepG2 cells. Relative luciferase activities in cell lysate were analyzed after 48 h treatment of blank vehicle or drugs to determine the induction activity toward CYP2B6 by various commonly used TCMs extract. The positive hPXR/hCAR activators rifampicin and CITCO were applied to make sure that the reporter gene model was successfully established. Then 5 kinds of commonly used TCM extracts and 1 herbal compound were successfully investigated, some were found to activate hPXR or hCAR and therefore have the potential to induce CYP2B6 enzyme. This is the first domestic article to report the hCAR3-mediated CYP2B6 induction model and the establishment of a reporter gene system for hPXR/CAR-mediated CYP2B6 induction can be an effective and systemic in vitro method to investigate the drug inducers of CYP2B6 and to explain the mechanism involved.
Aryl Hydrocarbon Hydroxylases ; genetics ; metabolism ; Cytochrome P-450 CYP2B6 ; Drugs, Chinese Herbal ; isolation & purification ; pharmacology ; Genes, Reporter ; Genetic Vectors ; Hep G2 Cells ; High-Throughput Screening Assays ; Humans ; Luciferases ; genetics ; metabolism ; Oximes ; pharmacology ; Plants, Medicinal ; chemistry ; Plasmids ; Receptors, Cytoplasmic and Nuclear ; genetics ; metabolism ; Receptors, Steroid ; genetics ; metabolism ; Rifampin ; pharmacology ; Thiazoles ; pharmacology ; Transfection