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1.
Drug Metab Pharmacokinet ; 34(3): 201-208, 2019 Jun.
Article in English | MEDLINE | ID: mdl-30992242

ABSTRACT

The objective of the present study was to investigate the effects of cytochrome b5 (cytb5) on the drug metabolism catalyzed by CYP2C9, CYP2C19 and CYP3A4. Activities of CYP2C9, CYP2C19, and CYP3A4 were determined by using the prototypical substrates tolbutamide, omeprazole and midazolam, respectively. Cytb5 protein and mRNA contents showed large inter-individual variations with 11- and 6-fold range, respectively. All of three P450s showed an increased activity in proportion to the amount of cytb5 expression. Particularly, CYP3A4 showed the strongest correlation between cytb5 protein amount and the activity, followed by CYP2C9 and CYP2C19. The putative splicing variant, c.288G>A (rs7238987) was identified and was screened in 36 liver tissues by direct DNA sequencing. Liver tissues having a splicing variant exhibited unexpected sizes of cytb5 mRNA and a decreased expression tendency of cytb5 protein compared to the wild-type. A decreased activity in the metabolism of the CYP2C19 substrate omeprazole was observed in liver tissues carrying the splicing variant when compared to the wild-type Cytb5 (P < 0.05). The present results propose that different expression of cytb5 can cause variations in CYP mediated drug metabolism, which may explain, at least in part, the inter-individual difference in drug responses in addition to the CYP genetic polymorphisms.


Subject(s)
Cytochrome P-450 CYP2C19/metabolism , Cytochrome P-450 CYP2C9/metabolism , Cytochrome P-450 CYP3A/metabolism , Cytochromes b5/genetics , Genetic Variation , Liver/metabolism , Alternative Splicing , Cytochrome P-450 CYP2C19/genetics , Cytochrome P-450 CYP2C9/genetics , Cytochrome P-450 CYP3A/genetics , Cytochromes b5/metabolism , Humans , In Vitro Techniques , Liver/enzymology , Midazolam/metabolism , Omeprazole/metabolism , Tolbutamide/metabolism
2.
Cancer Chemother Pharmacol ; 75(1): 173-82, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25417047

ABSTRACT

PURPOSE: Imatinib is a substrate of drug transporters and metabolizing enzymes, including members of the cytochrome P450 (CYP) system. Differences in imatinib pharmacokinetics among individuals might be influenced by genetic polymorphisms and be associated with variable clinical imatinib efficacy. This study sought to test how genetic polymorphisms can affect the clinical efficacy of imatinib and its blood levels in GIST patients. METHODS: A total of 209 GIST patients who had received imatinib 400 mg daily were genotyped for six single-nucleotide polymorphisms in three genes (CYP3A5 6986A>G; ABCB1 1236C>T, 2677G>A/T, and 3435C>T; and ABCG2 34G>A and 421C>A) via blood samples. Progression-free survival (PFS) and imatinib plasma trough levels were evaluated and compared according to genotypes. RESULTS: With a median follow-up of 39.6 months (range 16.7-97.5 months), the estimated 5-year PFS rate was 67.5 % (95 % CI 59.9-75.1). Among the CYP3A5, ABCB1, and ABCG2 genotypes, ABCG2 421C>A was associated with PFS. The 5-year PFS rate in patients with the AA variant of ABCG2 421C>A (92.3 %; 95 % CI 77.8-100.0) was significantly superior to that of patients with CC/CA genotypes (65.0 %; 95 % CI 56.9-73.1; p = 0.047). For the imatinib trough levels, there were no statistically significant differences when comparing polymorphisms among all genotypes, even after adjusting for clinical factors, including sex, age, body surface area, hemoglobin, albumin, and creatinine clearance. CONCLUSIONS: The ABCG2 421C>A genetic variation could influence clinical efficacy in terms of PFS in patients with advanced GIST undergoing imatinib therapy.


Subject(s)
ATP-Binding Cassette Transporters/genetics , Antineoplastic Agents/therapeutic use , Benzamides/therapeutic use , Gastrointestinal Neoplasms/drug therapy , Gastrointestinal Stromal Tumors/drug therapy , Neoplasm Proteins/genetics , Piperazines/therapeutic use , Polymorphism, Single Nucleotide , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , ATP Binding Cassette Transporter, Subfamily G, Member 2 , ATP-Binding Cassette Transporters/metabolism , Academic Medical Centers , Adult , Aged , Aged, 80 and over , Amino Acid Substitution , Antineoplastic Agents/blood , Antineoplastic Agents/pharmacokinetics , Benzamides/blood , Benzamides/pharmacokinetics , Female , Follow-Up Studies , Gastrointestinal Neoplasms/blood , Gastrointestinal Neoplasms/diagnosis , Gastrointestinal Neoplasms/genetics , Gastrointestinal Stromal Tumors/blood , Gastrointestinal Stromal Tumors/diagnosis , Gastrointestinal Stromal Tumors/genetics , Genetic Association Studies , Humans , Imatinib Mesylate , Male , Middle Aged , Neoplasm Proteins/metabolism , Piperazines/blood , Piperazines/pharmacokinetics , Prognosis , Protein Kinase Inhibitors/blood , Protein Kinase Inhibitors/pharmacokinetics , Pyrimidines/blood , Pyrimidines/pharmacokinetics , Republic of Korea , Retrospective Studies , Survival Analysis
3.
PLoS One ; 8(5): e64114, 2013.
Article in English | MEDLINE | ID: mdl-23737969

ABSTRACT

Transfusion-associated iron overload induces systemic toxicity. Deferasirox, a convenient long acting oral agent, has recently been introduced in clinical practice with a promising efficacy. But there are some patients who experience drug-related toxicities and cannot tolerate it. To investigate effect of genetic variations on the toxicities and find optimal target population, we analyzed the genetic polymorphisms of UDP-glucuronosyltransferase 1A (UGT1A) subfamily, multi-drug resistance-associated protein 2 (MRP2) and breast cancer resistance protein (BCRP). A total of 20 functional genetic polymorphisms were analyzed in 98 patients who received deferasirox to reduce transfusion-induced iron overload. We retrospectively reviewed the medical records to find out the drug-related toxicities. Fifteen (15.3%) patients developed hepatotoxicity. Patients without wild-type allele carrying two MRP2 haplotypes containing -1774 del and/or -24T were at increased risk of developing hepatotoxicity compared to patients with the wild-type allele on multivariate analysis (OR = 7.17, 95% CI = 1.79-28.67, P = 0.005). Creatinine elevation was observed in 9 patients (9.2%). Body weight ≥40 kg and homozygosity for UGT1A1*6 were risk factors of creatinine elevation (OR = 8.48, 95% CI = 1.7-43.57, P = 0.010 and OR = 14.17, 95% CI = 1.34-150.35, P = 0.028). Our results indicate that functional genetic variants of enzymes to metabolize and transport deferasirox are associated with drug-related toxicities. Further studies are warranted to confirm the results as the pharmacogenetic biomarkers of deferasirox.


Subject(s)
Benzoates/adverse effects , Iron Chelating Agents/adverse effects , Pharmacogenetics , Triazoles/adverse effects , ATP Binding Cassette Transporter, Subfamily G, Member 2 , ATP-Binding Cassette Transporters/genetics , Adolescent , Child , Child, Preschool , Creatinine/blood , Deferasirox , Female , Glucuronosyltransferase/genetics , Humans , Infant , Liver/drug effects , Male , Multidrug Resistance-Associated Protein 2 , Multidrug Resistance-Associated Proteins/genetics , Neoplasm Proteins/genetics , Polymorphism, Genetic , Young Adult
4.
Drug Metab Dispos ; 41(4): 888-96, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23378627

ABSTRACT

Human constitutive androstane receptor (hCAR, NR1I3) is a member of the orphan nuclear receptor family and regulates the transcription of many drug-metabolizing enzymes and drug transporters. Previous studies have shown that the hCAR gene produces a number of different kinds of mRNA splicing variants (SVs) in non-Asian ethnicities. In the present study, we identified 18 hCAR SVs (SV1-SV18), including four novel SVs in Korean human livers. Among the four novel SVs, SV2 showed enhanced transactivation activity when cotransfected with CYP2B6 reporter gene, whereas other SVs were nonfunctional. When profiles of major hCAR SVs were compared among 30 livers from Korean patients and 20 livers from Caucasian patients, the relative composition of each SV showed interethnic variation as well as interindividual variation. The most predominant form of hCAR SV was not wild type, but either SV4 or SV7. The summed relative amounts of SV4 and SV7 ranged from 34.5 to 57.6% in the 30 Korean livers and from 47.2 to 82.6% in the 20 Caucasian livers, suggesting large interindividual variation. The mean relative amount of nonfunctional SV9 was significantly higher in Koreans (29.8%) than in Caucasians (12.8%). The mean relative amount of novel SV2 was 9.7% in Korean livers and 3.5% in Caucasian livers. Expression profiling of hCAR proteins in human livers also supported large interindividual variation in the expressional ratio of wild-type and SVs. Our results describe for the first time the direct comparison of hCAR SV profiles between Koreans and Caucasians. The functional relevance of these interindividual and interethnic variations of hCAR mRNA expression needs to be further characterized.


Subject(s)
Alternative Splicing/genetics , Asian People/genetics , Liver/metabolism , Receptors, Cytoplasmic and Nuclear/genetics , White People/genetics , Adult , Aged , Constitutive Androstane Receptor , Female , Gene Expression Profiling , Hep G2 Cells , Humans , Male , Middle Aged
5.
Drug Metab Pharmacokinet ; 28(4): 372-7, 2013.
Article in English | MEDLINE | ID: mdl-23358261

ABSTRACT

SULT1A1 and SULT1A2 are encoded on the same chromatid, and exhibit a 96% amino acid similarity. To screen for genetic variants in these two closely related genes, SULT1A1 and SULT1A2 were directly sequenced in 50 healthy Koreans. A total of 30 variations were identified in SULT1A1: eight in exons, thirteen in introns, and nine in the 5'-untranslated region. With regard to SULT1A2, 21 variants were identified, comprising seven in exons, five in introns, and nine in the 5'-untranslated region. Among these 51 variations, one in SULT1A1 and eight in SULT1A2 were previously unidentified, which include three coding variants (SULT1A2 R37Q, 110G>A; SULT1A2 G50S, 148G>A; SULT1A2 F286L, 3819C>A) and one null allele (SULT1A2 E217Stop, 3542G>T). Two LD blocks, major haplotype structures, and 7 haplotype-tagging SNPs were determined together for SULT1A1 and SULT1A2 as a single set. Frequencies of common functional variants were compared among ethnic groups. Since these two SULT enzymes are on the same chromatid in a parallel direction with overlapping substrate specificities, a combined analysis using LD and haplotype-tagging single-nucleotide polymorphisms (SNPs) will facilitate understanding of the variations in the sulfation reactions of a wide range of substrates, as compared with analysis of individual genes.


Subject(s)
Arylsulfotransferase/genetics , Asian People/genetics , Ethnicity/genetics , Humans , Linkage Disequilibrium , Polymorphism, Single Nucleotide , Republic of Korea
6.
Pharmacogenet Genomics ; 23(3): 175-9, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23292115

ABSTRACT

Hepatocyte nuclear receptor 4α (HNF4α) plays a central role in regulating human drug-metabolizing enzymes. Our previous study suggested that the newly identified polymorphism G60D in the HNF4α gene may decrease its downstream CYP2D6 activity in Asians. To confirm this effect in a clinical setting, we carried out a full pharmacokinetic study of a single oral dose of CYP2D6 substrate tolterodine in 30 healthy Korean individuals (HNF4α wild type: n = 24; HNF4α G60D heterozygotes: n = 6) who were pregenotyped for CYP2D6. Our study showed HNF4α G60D to be an independent predictor for increased AUC0-∞, C max of tolterodine and increased AUC0-∞ of the active moiety (tolterodine+5-hydroxymethyl-tolterodine) (P<0.05). A significant proportion of the variance in these parameters (R = 0.81, 0.59, and 0.63, respectively; P<0.01) was explained together by CYP2D6 and HNF4α genotypes. Further investigation of HNF4α genetic polymorphisms may improve the predictability of CYP2D6 activity in different populations.


Subject(s)
Benzhydryl Compounds/pharmacokinetics , Cresols/pharmacokinetics , Cytochrome P-450 CYP2D6/metabolism , Hepatocyte Nuclear Factor 4/genetics , Muscarinic Antagonists/pharmacokinetics , Phenylpropanolamine/pharmacokinetics , Polymorphism, Genetic , Humans , Republic of Korea , Substrate Specificity , Tolterodine Tartrate
7.
Br J Clin Pharmacol ; 75(1): 244-53, 2013 Jan.
Article in English | MEDLINE | ID: mdl-22554354

ABSTRACT

AIMS: To evaluate the effects of clopidogrel and itraconazole on the disposition of efavirenz and its hydroxyl metabolites in relation to the CYP2B6*6 genotype and explore potential phenotyping indices for CYP2B6 activity in vivo using a low dose of oral efavirenz. METHODS: We conducted a randomized three phase crossover study in 17 healthy Korean subjects pre-genotyped for the CYP2B6*6 allele (CYP2B6*1/*1, n = 6; *1/*6, n = 6; *6/*6, n = 5). Subjects were pretreated with clopidogrel (75 mg day(-1) for 4 days), itraconazole (200 mg day(-1) for 6 days), or placebo and then given a single dose of efavirenz (200 mg). The plasma (0-120 h) and urine (0-24 h) concentrations of efavirenz and its metabolites (7- and 8-hydroxyefavirenz and 8,14-dihydroxyefavirenz) were determined by LC/MS/MS. RESULTS: This study is the first to delineate quantitatively the full (phase I and II) metabolic profile of efavirenz and its three hydroxyl metabolites in humans. Clopidogrel pretreatment markedly decreased AUC(0,48 h), C(max) and Ae(0,24 h) for 8,14-dihydroxyefavirenz, compared with placebo; 95% CI of the ratios were 0.55, 0.73, 0.30, 0.45 and 0.25, 0.47, respectively. The 8,14-dihydroxyefavirenz : efavirenz AUC(0,120 h) ratio was significantly correlated with the weight-adjusted CL/F of efavirenz (r(2) ≈ 0.4, P < 0.05), differed with CYP2B6*6 genotype and was affected by clopidogrel pretreatment (P < 0.05) but not by itraconazole pretreatment. CONCLUSIONS: The disposition of 8,14-dihydroxy-EFV appears to be sensitive to CYP2B6 activity alterations in human subjects. The 8,14-dihydroxyefaviremz : efavirenz AUC(0,120 h) ratio is attractive as a candidate phenotyping index for CYP2B6 activity in vivo.


Subject(s)
Anti-HIV Agents/pharmacokinetics , Antifungal Agents/pharmacology , Aryl Hydrocarbon Hydroxylases/genetics , Benzoxazines/pharmacokinetics , Itraconazole/pharmacology , Oxidoreductases, N-Demethylating/genetics , Platelet Aggregation Inhibitors/pharmacology , Ticlopidine/analogs & derivatives , Alkynes , Clopidogrel , Cross-Over Studies , Cyclopropanes , Cytochrome P-450 CYP2B6 , Genotype , Humans , Hydroxylation , Male , Phenotype , Ticlopidine/pharmacology
8.
Xenobiotica ; 43(2): 211-8, 2013 Feb.
Article in English | MEDLINE | ID: mdl-22830954

ABSTRACT

Plasma concentrations of sibutramine and its two active metabolites after single oral dose of sibutramine were determined in Korean healthy male subjects with different CYP2B6 genotypes (CYP2B6*1/*1, *1/*6 and *6/*6), either alone or after four-day pretreatment with clopidogrel or clarithromycin. The pretreatment with clopidogrel and clarithromycin raised the mean area under the concentration-time curve (AUC) of sibutramine by 163% and 255%, respectively. Co-administration of clarithromycin, combined with CYP2B6*6/*6 genotype, led to highest concentration of sibutramine. The molar sum AUC (M1 + M2) was raised by 35% in the clopidogrel phase but not significantly affected by clarithromycin or CYP2B6 genotype. The CYP2B6*6/*6 subjects in the clopidogrel phase showed the highest molar AUC (M1 + M2) among three genotype groups throughout the three phases. The exposure of sibutramine and its metabolites seemed to be associated with the CYP2B6 genotype. The treatment of clopidogrel significantly altered the disposition of active metabolites as well as sibutramine, but clarithromycin only affects the disposition of sibutramine. These results suggest that the perturbation of CYP2B6 activity may contribute to the inter-individual variation of sibutramine drug responses although the clinical relevance is remained to be established.


Subject(s)
Appetite Depressants/metabolism , Aryl Hydrocarbon Hydroxylases/genetics , Clarithromycin/pharmacology , Cyclobutanes/metabolism , Oxidoreductases, N-Demethylating/genetics , Ticlopidine/analogs & derivatives , Anti-Bacterial Agents/pharmacology , Appetite Depressants/pharmacokinetics , Aryl Hydrocarbon Hydroxylases/antagonists & inhibitors , Aryl Hydrocarbon Hydroxylases/metabolism , Asian People , Clopidogrel , Cyclobutanes/pharmacokinetics , Cytochrome P-450 CYP2B6 , Humans , Male , Oxidoreductases, N-Demethylating/antagonists & inhibitors , Oxidoreductases, N-Demethylating/metabolism , Platelet Aggregation Inhibitors/pharmacology , Polymorphism, Genetic , Republic of Korea , Ticlopidine/pharmacology
9.
Mol Nutr Food Res ; 56(5): 797-809, 2012 May.
Article in English | MEDLINE | ID: mdl-22648626

ABSTRACT

SCOPE: Capsaicin (8-methyl-N-vanillyl-6-nonenamide) is the principal pungent ingredient in hot red and chili peppers. Many studies have focused on the anticarcinogenic or chemopreventive activities of capsaicin. However, the influence of capsaicin on CYP3A4, its involvement in drug metabolism, and the underlying mechanisms remain unclear. METHODS AND RESULTS: Here, we examined the effect of capsaicin on CYP3A4 expression and the metabolism of CYP3A1 substrate, nifedipine in male Sprague-Dawley rats. Capsaicin induced the enzymatic activity and expression of CYP3A4 in HepG2 cells. Treatment with a human pregnane X receptor (hPXR) inhibitor reduced the inductive effects of capsaicin on CYP3A4 expression. Capsaicin also induced the activation of CCAAT/enhancer-binding protein ß (C/EBPß). Moreover, capsaicin increased the activation of the transient receptor potential vanilloid type-1 receptor downstream signaling components Ca²âº/calmodulin-dependent protein kinase and Akt. Capsaicin elevated the level of CYP3A1 in rat liver and significantly increased the biotransformation of nifedipine to dehydronifedipine. CONCLUSION: From these data, we conclude that capsaicin induces CYP3A4 expression in vitro and in vivo. This induction was achieved by the activation of hPXR and C/EBPß. Our results suggest that capsaicin might induce CYP3A4 expression; thus, exposure to capsaicin may increase the metabolism of CYP3A4 substrate and potentially cause food-drug interactions.


Subject(s)
CCAAT-Enhancer-Binding Protein-beta/genetics , Capsaicin/pharmacology , Cytochrome P-450 CYP3A/genetics , Receptors, Steroid/genetics , Animals , CCAAT-Enhancer-Binding Protein-beta/metabolism , Cytochrome P-450 CYP3A/metabolism , Food-Drug Interactions , Gene Expression Regulation/drug effects , Hep G2 Cells , Humans , Inactivation, Metabolic , Liver/drug effects , Liver/metabolism , Male , Nifedipine/analogs & derivatives , Nifedipine/blood , Nifedipine/pharmacokinetics , Pregnane X Receptor , Promoter Regions, Genetic/drug effects , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Steroid/metabolism , Signal Transduction/drug effects , TRPV Cation Channels/metabolism , Up-Regulation
10.
Drug Metab Pharmacokinet ; 27(5): 530-5, 2012.
Article in English | MEDLINE | ID: mdl-22498645

ABSTRACT

To clarify inter-individual variation in the expression of organic cation transporter 1 (OCT1), the levels of OCT1 mRNA and protein from 65 human liver samples were examined by real-time PCR and Western blot analysis and were associated with OCT1 genotypes. The expression levels of OCT1 mRNA and protein in 65 liver samples of Korean origin were not normally distributed and varied by 23.6- and 15.9-fold, respectively. OCT1 mRNA expression was correlated with OCT1 protein expression with a correlation coefficient of 0.641 (p < 0.0001). However, non-genetic factors, such as age, gender, and cholestasis, were not significantly associated with OCT1 expression. When quantitative expression levels were compared in relation to OCT1 promoter SNPs, there was no significant difference in OCT1 expression levels among the -1795 GG, GA, and AA genotypes. Moreover, expression levels of OCT1 were not changed in relation to the -1756 genotypes. Inter-individual variation in OCT1 mRNA and protein expression levels in the liver did not correlate with OCT1 genotypes or non-genetic factors, such as age, gender, and cholestasis. These results suggest that genetic and non-genetic factors may not be a significant contributing factor of variations in OCT1 expression from liver samples of Korean origin.


Subject(s)
Asian People/genetics , Liver/physiology , Organic Cation Transporter 1/biosynthesis , Organic Cation Transporter 1/genetics , Female , Genotype , Humans , Individuality , Liver/metabolism , Male , Middle Aged , Organic Cation Transporter 1/metabolism , Polymorphism, Single Nucleotide , RNA, Messenger/genetics , Republic of Korea
11.
J Korean Med Sci ; 26(8): 1007-13, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21860550

ABSTRACT

The aim of the study was to evaluate the association between genetic polymorphisms of CYP2D6 and outcomes in breast cancer patients with tamoxifen treatment. We evaluated the CYP2D6 genetic polymorphisms in 766 breast cancer patients. Among them, 110 patients whose samples were prospectively collected before surgery and treated with tamoxifen were included to evaluate the association between CYP2D6 and outcomes. The genotypes of CYP2D6 were categorized as extensive metabolizer (EM), intermediate metabolizer (IM), and poor metabolizer (PM) according to the activity score. The clinicopathologic features of 110 patients were not significantly different among the three groups except for the T-stage and nodal status. The high T-stage and axillary metastasis were more frequent in the PM group. While recurrence-free and overall survival in the PM group was poorer than the other groups, there was no significant difference between the EM and the IM group. The difference between the PM and the other groups on univariate analysis disappeared on multivariate analysis. These conflicting results suggest that the clinical value of CYP2D6 polymorphisms is still unclear and more large-sized and comprehensively designed trials are necessary.


Subject(s)
Antineoplastic Agents, Hormonal/therapeutic use , Breast Neoplasms/genetics , Cytochrome P-450 CYP2D6/genetics , Polymorphism, Single Nucleotide , Tamoxifen/therapeutic use , Adult , Aged , Aged, 80 and over , Breast Neoplasms/drug therapy , Breast Neoplasms/mortality , Female , Genotype , Humans , Kaplan-Meier Estimate , Middle Aged , Neoplasm Staging
12.
Xenobiotica ; 41(6): 501-10, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21341987

ABSTRACT

Genetic variants of Na(+)-taurocholate co-transporting polypeptide (NTCP; SLC10A1) and ileal apical sodium-dependent bile acid transporter (ASBT; SLC10A2), which greatly contribute to bile acid homeostasis, were extensively explored in the Korean population and functional variants of NTCP were compared among Asian populations. From direct DNA sequencing, six SNPs were identified in the SLC10A1 gene and 14 SNPs in the SLC10A2 gene. Three of seven coding variants were non-synonymous SNPs: two variants from SLC10A1 (A64T, S267F) and one from SLC10A2 (A171S). No linkage was analysed in the SLC10A1 gene because of low frequencies of genetic variants, and the SLC10A2 gene was composed of two separated linkage disequilibrium blocks contrary to the white population. The stably transfected NTCP-A64T variant showed significantly decreased uptakes of taurocholate and rosuvastatin compared with wild-type NTCP. The decreased taurocholate uptake and increased rosuvastatin uptake were shown in the NTCP-S267F variant. The allele frequencies of these functional variants were 1.0% and 3.1%, respectively, in a Korean population. However, NTCP-A64T was not found in Chinese and Vietnamese subjects. The frequency distribution of NTCP-S267F in Koreans was significantly lower than those in Chinese and Vietnamese populations. Our data suggest that NTCP-A64T and -S267F variants cause substrate-dependent functional change in vitro, and show ethnic difference in their allelic frequencies among Asian populations although the clinical relevance of these variants is remained to be evaluated.


Subject(s)
Organic Anion Transporters, Sodium-Dependent/genetics , Polymorphism, Single Nucleotide , Symporters/genetics , Asian People , Bile/metabolism , Fluorobenzenes/metabolism , Gene Frequency , Genomic Structural Variation , Humans , Linkage Disequilibrium , Organic Anion Transporters, Sodium-Dependent/metabolism , Pyrimidines/metabolism , Rosuvastatin Calcium , Sulfonamides/metabolism , Symporters/metabolism , Taurocholic Acid/metabolism
13.
Drug Metab Dispos ; 39(4): 711-6, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21245287

ABSTRACT

The objectives of this study were to identify the genetic variants of CYP2C8, analyze CYP2C8 single nucleotide polymorphisms (SNPs), and characterize their functional consequences in the CYP2C8 substrate drug rosiglitazone in humans. The direct full sequencing of CYP2C8 genomic DNA was performed in a Korean population (n = 50). A total of 17 CYP2C8 variants including a novel coding variant (E274Stop) were identified. The novel CYP2C8 E274Stop variant was assigned as CYP2C8*11 by the Human Cytochrome P450 (CYP) Allele Nomenclature Committee. Seventeen SNPs were used to characterize linkage disequilibrium, haplotype structures, and haplotype tagging SNPs. Genotyping for CYP2C8*11 in an extended set of Koreans (n = 400), whites (n = 100), Han Chinese (n = 348), Vietnamese (n = 100), and African Americans (n = 93) was performed by a newly developed pyrosequencing method. The frequency of CYP2C8*11 was 0.3% in Koreans, 1% in Vietnamese, and 0.14% in Chinese. However, none of the whites or African Americans contained the CYP2C8*11 allele. Subjects with CYP2C8*1/*11 exhibited higher plasma concentration-time profiles of rosiglitazone than those of nine control subjects carrying CYP2C8*1/*1. The area under the concentration-time curve and peak plasma concentration of rosiglitazone in individuals carrying CYP2C8*1/*11 (n = 5) were 54 and 34% higher than the mean values observed in the control subjects carrying CYP2C8*1/*1 (P = 0.015 and P = 0.025, respectively). In summary, this is the first report to characterize the allele frequency and haplotype distribution of CYP2C8 in a Korean population, and it provides functional analysis of a new variant CYP2C8*11. Our findings suggest that individuals carrying CYP2C8*11, a null allele found in Asians only, may have lower activity for metabolizing CYP2C8 substrate drugs.


Subject(s)
Aryl Hydrocarbon Hydroxylases/genetics , Hypoglycemic Agents/pharmacokinetics , Polymorphism, Single Nucleotide , Thiazolidinediones/pharmacokinetics , Adult , Alleles , Aryl Hydrocarbon Hydroxylases/metabolism , Asian People/genetics , Cytochrome P-450 CYP2C8 , Gene Frequency , Genotype , Haplotypes , Humans , Hypoglycemic Agents/blood , Hypoglycemic Agents/metabolism , Korea , Linkage Disequilibrium , Rosiglitazone , Thiazolidinediones/blood , Thiazolidinediones/metabolism , Young Adult
14.
Thromb Res ; 127(3): 220-7, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21216445

ABSTRACT

INTRODUCTION: Although P2Y12 has a significant role in normal hemostasis and thrombosis, no genetic study has been described about the association between P2Y12 variants and the extent of ADP-induced platelet activation in the Korean population. MATERIALS AND METHODS: The expression levels of two reference sequences of P2Y12 mRNA transcripts (variants 1 and 2) were examined in the whole blood before direct DNA sequencing. The subjects were screened for single-nucleotide polymorphisms (SNPs) in P2Y12 by direct DNA sequencing (n=50). Frequencies of P2Y12 single nucleotide polymorphisms (SNPs), linkage disequilibrium blocks, haplotype structures, and haplotype-tagging SNPs were determined. The effects of genetic variation in the P2Y12 gene on the extent of ADP-induced platelet aggregation were studied in healthy Korean men (n=40). RESULTS: Variant 2 (NM 176876.1) was the predominantly expressed form in all subjects, but variant 1 was also weakly expressed in all cases (n=10). A total of 20 SNPs were identified: 2 in exons, 5 in introns, and 8 and 5 in the 5'-untranslated regions of the known P2Y12 RNA variants 1 and 2, respectively. Genetic analysis of the P2Y12 SNPs and haplotypes revealed a statistically significant association between P2Y12 haplotype, denoted H3, and an increase in the ADP-induced platelet aggregation response relative to that for the reference haplotype H1 (P=0.01). CONCLUSIONS: Application of these findings to the development of a multivariate model might be useful in explaining the variable outcome of antiplatelet drug therapy in Asian populations.


Subject(s)
Adenosine Diphosphate/metabolism , Platelet Aggregation , Polymorphism, Single Nucleotide , Receptors, Purinergic P2Y12/genetics , Adult , Haplotypes , Humans , Korea , Linkage Disequilibrium , Male , Young Adult
15.
Clin Chim Acta ; 411(23-24): 2043-8, 2010 Dec 14.
Article in English | MEDLINE | ID: mdl-20828547

ABSTRACT

BACKGROUND: We developed a CYP2D6 genotyping method that includes copy number variation (CNV) and recently known functional haplotypes using multiplex single-base extension (SBE). METHODS: Twelve CYP2D6 alleles (*1, *2, *5, *10, *14, *18, *21, *41, *49, *52, *60, and a duplication of CYP2D6) were genotyped using 2 PCR reactions followed by multiplex SBE with 10 primers and singleplex SBE with 1 primer. The result from 758 Korean samples was validated by comparison with the results of direct sequencing or other genotyping methods. We also genotyped 89 Chinese and 122 Vietnamese subjects to determine the presence of recently identified functional alleles. RESULTS: All 12 CYP2D6 alleles, including gene deletion and duplication, were obviously discriminated. The concordance rate was 100% between our method and other methods. Our method also covered over 98% of the CYP2D6 genotypes in Japanese and Chinese subjects based on reported data. In addition to published genotypes, *14, *21, *41, *49, and *52 were found in about 5% in Chinese and Vietnamese. CONCLUSIONS: The CYP2D6 genotyping method may be clinically applicable for Asian populations. The method can be improved easily to cover other ethnic groups by utilizing additional haplotype tagging SNPs.


Subject(s)
Asian People/genetics , Cytochrome P-450 CYP2D6/genetics , DNA Copy Number Variations/genetics , Genetic Techniques , Base Sequence , Gene Frequency , Genotype , Humans , Polymorphism, Single Nucleotide/genetics
16.
Br J Clin Pharmacol ; 70(2): 213-21, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20653674

ABSTRACT

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT * CYP2C9 single nucleotide polymorphisms (SNPs) are important in safe and effective oral anticoagulation with warfarin use. * Although CYP2C9*2 and *3 are important genetic factors for the warfarin dose, one of the CYP2C9 SNPs, IVS-65G>C, has been suggested to be associated with warfarin sensitivity. However, as of yet, there has been no explanation about the possible mechanism and linkage analysis. WHAT THIS PAPER ADDS * New information on CYP2C9 SNPs and their occurrences in common haplotype structures in healthy unrelated Koreans and in individuals who require low warfarin dose after mechanical heart valve replacements (MHVRs) were studied. * Additional evidence showed that an Asian dominant haplotype consisting of -1565C>T, -1188T>C, IVS3+197G>A, IVS3-334C>T, IVS3-65G>C, IVS4-115A>G and IVS5-73A>G could be associated with a low warfarin maintenance dose in mechanical heart valve replacement (MHVR) patients. AIMS The objectives of this study were to determine the distribution of CYP2C9 variants in Koreans and investigate their association with warfarin dose requirements in patients who received MHVRs. METHODS All nine exons, intron-exon junction, and promoter region of CYP2C9 were amplified and directly sequenced in 50 healthy normal Koreans. Additional direct DNA sequencing of the CYP2C9 gene was conducted in 36 of the 267 MHVR patients who required low maintenance warfarin doses without carrying CYP2C9*3 and VKORC1 1173T mutations. The effects of CYP2C9 genetics on warfarin maintenance dose were assessed in 267 MHVR patients. RESULTS Thirty-nine single nucleotide polymorphisms (SNPs) including seven previously unidentified SNPs were identified in 50 Koreans by direct DNA sequencing. One of the CYP2C9 haplotypes exhibited an association with warfarin low dose requirement. The adjusted odds ratio for the haplotype between the low dose group and the normal subjects was 2.5 (95% confidence interval 1.05, 6.16). This haplotype consisting of -1565C>T, -1188T>C, IVS3+197G>A, IVS3-334C>T, IVS3-65G>C, IVS4-115A>G, and IVS5-73A>G was found in 15% of 36 MHVR patients who required low warfarin doses, while 4% of 50 normal healthy subjects exhibited this haplotype. One of the SNPs comprising this haplotype, -1565C>T, apparently changed a protein binding pattern as observed in electrophoretic mobility shift assay. CONCLUSION The haplotype including -1565C>T, -1188T>C, IVS3+197G>A, IVS3-334C>T, IVS3-65G>C, IVS4-115A>G, and IVS5-73A>G seems to be associated with low warfarin dose requirement and this haplotype could be considered in the development of a warfarin dose prediction model for Asian populations.


Subject(s)
Anticoagulants/pharmacology , Aryl Hydrocarbon Hydroxylases/genetics , Genotype , Heart Valve Prosthesis Implantation , Polymorphism, Single Nucleotide/genetics , Warfarin/pharmacology , Asian People/genetics , Cytochrome P-450 CYP2C9 , DNA Mutational Analysis , Exons , Gene Frequency , Heart Diseases/genetics , Heart Diseases/surgery , Humans , Introns , Korea , Promoter Regions, Genetic/genetics , Sequence Analysis, DNA
17.
J Hum Genet ; 55(3): 189-93, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20186154

ABSTRACT

Aromatase, encoded by the CYP19A1 gene, is a key enzyme in the biosynthesis of estrogen. In an effort to screen for CYP19A1 single-nucleotide polymorphisms (SNPs) in Koreans, the CYP19A1 gene was directly sequenced in 50 normal subjects. A total of 19 variations were identified: four in exons, ten in introns, six in the 5'-untranslated region (UTR) and one in 3'-UTR. The distribution of CYP19A1 (TTTA)(n) polymorphisms was such that the most frequent allele was (TTTA)(7) (66%), followed by (TTTA)(11) (30%), (TTTA)(12) (3%) and (TTTA)(13) (1%). The order of the frequency distribution of CYP19A1 variations, other than that of the (TTTA)(n) variant, was IVS6-106T>G and IVS7-79A>G (57%); 1531C>T (56%); IVS5-16T>G and IVS6+36A>T (54%); -196A>C and -77G>A (49%); IVS2-59A>G and 240A>G (48%); -278C>T (31%); IVS4+27TCTI>D (29%); -144C>T and -588G>A (19%); 790C>T (16%); and other minor alleles with less than 5% frequency. Nineteen variations were used to characterize linkage disequilibrium (LD) structures at the CYP19A1 locus, which resulted in three LD blocks. Eight tagging SNPs in CYP19A1 were determined. Identification of CYP19A1 SNPs with LD blocks and tagging SNPs creates an important resource for genotype-phenotype association studies for estrogen-related phenotypes.


Subject(s)
Aromatase/genetics , Asian People/genetics , Haplotypes/genetics , Polymorphism, Single Nucleotide/genetics , Case-Control Studies , Gene Frequency/genetics , Genome, Human/genetics , Humans , Linkage Disequilibrium/genetics , Republic of Korea
18.
Clin Chim Acta ; 411(1-2): 99-105, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19854166

ABSTRACT

BACKGROUND: Organic anion transporters (OATs) play an essential role in the disposition of numerous organic anions. To clarify the interindividual variation in the function of OATs, genetic polymorphisms of the SLC22A6 and SLC22A7 in Korean subjects were investigated and associated with hepatic hOAT2 expression and the SLC22A7 genotype. METHODS: The genetic variants and their frequencies for the SLC22A6 and SLC22A7 genes in 50 Korean subjects were investigated by direct sequencing. The expression of hOAT2 protein from 34 human liver samples was examined by western blot analysis. RESULTS: Eight SNPs including 2 novel SNPs were identified in the SLC22A6 gene and eight SNPs including 4 novel SNPs were identified in the SLC22A7 gene. No amino acid alteration was found. Linkage disequilibrium (LD) analysis revealed that the SLC22A6 and SLC22A7 genes have separated single LD blocks and consist of a limited number of haplotypes (14 haplotypes for SLC22A6 and 5 haplotypes for SLC22A7). The expression of the hOAT2 protein varied 10-fold among 34 human livers but was not associated with the SLC22A7 genotype (p=0.16). CONCLUSIONS: The SLC22A7 genomic sequences showed low variability. A 10-fold variation in hOAT2 protein expression in the liver specimens was not correlated with SLC22A7 genotypes. These results suggest that genetic polymorphisms may not be a significant contributing factor to variations in the hOAT2 expression or hOAT2 transport activity.


Subject(s)
Liver/metabolism , Organic Anion Transport Protein 1/genetics , Organic Anion Transporters, Sodium-Independent/genetics , Polymorphism, Single Nucleotide , Base Sequence , Blotting, Western , DNA Primers , Genotype , Haplotypes , Humans , Linkage Disequilibrium , Republic of Korea
19.
J Clin Pharmacol ; 50(2): 195-204, 2010 Feb.
Article in English | MEDLINE | ID: mdl-19841159

ABSTRACT

The present study was performed to elucidate the effects of itraconazole and rifampin on the pharmacokinetics and pharmacodynamics of ebastine, a nonsedative H1 receptor antagonist. In a 3-way crossover sequential design with 2-week washouts, 10 healthy participants were pretreated with itraconazole for 6 days, rifampin for 10 days, or neither. After oral administration of 20 mg ebastine, blood and urine samples were collected for 72 and 24 hours, respectively, and histamine-induced wheal and flare reactions were measured to assess the antihistamine response for 12 hours. Itraconazole pretreatment decreased the oral clearance of ebastine to 10% (P < .001) and increased the AUC(infinity) of the active metabolite, carebastine, by 3-fold (P < .001). On the other hand, rifampin pretreatment decreased the AUC(infinity) of carebastine to 15% (P < .001), with an enormous reduction in the oral bioavailability of ebastine and significantly reduced histamine-induced skin reactions. From these results, the disposition of ebastine and carebastine seems to be significantly altered by coadministration of itraconazole or rifampin. The antihistamine response after ebastine dosing would be decreased following rifampin pretreatments.


Subject(s)
Butyrophenones/metabolism , Butyrophenones/pharmacokinetics , Itraconazole/pharmacology , Piperidines/metabolism , Piperidines/pharmacokinetics , Rifampin/pharmacology , Adult , Antifungal Agents/pharmacology , Butyrophenones/therapeutic use , Cross-Over Studies , Drug Interactions , Enzyme Inhibitors/pharmacology , Histamine/adverse effects , Histamine H1 Antagonists/pharmacokinetics , Histamine H1 Antagonists/therapeutic use , Humans , Hypersensitivity, Immediate/chemically induced , Hypersensitivity, Immediate/drug therapy , Male , Piperidines/therapeutic use , Skin/immunology , Young Adult
20.
Mol Biol Rep ; 37(1): 213-7, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19585271

ABSTRACT

Cytochrome P450 3A7 (CYP3A7) is expressed in the human fetal liver and plays a role in the metabolism of hormones, drugs, and toxic compounds. Genetic variants of CYP3A7 are associated with serum estrone level, bone density, and hepatic CYP3A activity in adults. We analyzed the genetic variations of CYP3A7 in a Korean population. From direct sequencing of all exons and flanking regions of the CYP3A7 gene in 48 Koreans, we found five genetic variants, including three novel variants. One variant, a thymidine insertion in exon 2 (4011insT), causes premature termination of CYP3A7 translation, which may result in a null phenotype. The novel variant was assigned to the CYP3A7*3 allele by the CYP allele nomenclature committee. For further screen of this novel variant in other ethnic populations, we used pyrosequencing to analyze an additional 185 Koreans, 100 African Americans, 100 Caucasians, and 159 Vietnamese for the presence of this variant. The variant was not found in any other individuals, except for one Korean subject. The frequencies of two known functional alleles, CYP3A7*2 and CYP3A7*1C, were 26 and 0%, respectively, in Koreans. The frequencies of the functional CYP3A7 polymorphisms in Koreans were significantly different from those in Caucasians and African Americans. This is the first report of a null-type allele of the CYP3A7 gene. It also provides population-level genetic data on CYP3A7 in Koreans to reveal the wide ethnic variation in CYP3A7 polymorphism.


Subject(s)
Alleles , Aryl Hydrocarbon Hydroxylases/genetics , Asian People/genetics , Polymorphism, Genetic , Base Sequence , Cytochrome P-450 CYP3A , DNA Mutational Analysis , Heterozygote , Humans , Molecular Sequence Data , Republic of Korea
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