• Journal of Life Science
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• v.20 no.5
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• pp.799-804
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• 2010

In humans, CYP2C19, a member of the cytochrome P450 subfamily, metabolizes arachidonic acid to produce epoxyicosanoid acids, which are involved in vascular tone and regulation of blood pressure (BP). Recent findings suggest that CYP2C19 gene polymorphisms might be considered as a novel candidate gene for cardiovascular disease. We thus focused on the Korean population to explore the association of two polymorphisms ($CYP2C19^*2$ and $^*3$) in this gene and essential hypertension (EH). A total of 1,241 participants (537 hypertensive subjects and 704 healthy controls) were recruited from the Yonsei Cardiovascular Genome Center in Korea. The CYP2C19 polymorphisms were genotyped using the $SNaPShot^{TM}$ assay. The allele and genotype frequencies of $CYP2C19^*3$ showed significant difference between hypertensives and normotensives (P=0.019 and P=0.023, respectively). Logistic regression analysis indicated that the $CYP2C19^*3$ A allele carriers were significantly associated with EH (OR, 0.723; 95% CI, 0.538-0.972, P=0.032) under a dominant model. In addition, CYP2C19 G-A haplotype ($2C19^*2\;G-^*3$ A combination) was found to significantly reduce EH risk (OR, 0.714, P=0.015). We believe this provides evidence that $CYP2C19^*3$ polymorphism may contribute to a protective effect in the development of EH.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.19
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• pp.8331-8335
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• 2014

Background: Previous studies accessing the association of CYP2C19 with outcomes of patients using tamoxifen for breast cancer have yielded conflicting results. The aim of this meta-analysis is to obtain a more precise estimate of effects of CYP2C19 polymorphisms and to clarify their effects on survival of the breast cancer patients using tamoxifen. Materials and Methods: A systematic search of PubMed and Embase was performed, comparing patients with or without $CYP2C19^*2$ and $CYP2C19^*17$, relevant articles searched for. The following outcomes were included from the eligible studies: disease-free survival (DFS) and overall survival (OS), expressed by hazard ratios (HR) with corresponding 95% confidence interval (CI). Subgroup analysis by genotypes was also performed. Pooled estimates were calculated using random-effect model in accordance to the heterogeneity. Results: Six studies met the inclusion criteria. The integrated OR on the association between CYP2C19 and DFS, calculated by the random-effect model, was 0.54 (95%CI=0.34-0.84, p=0.013). Subgroup analysis showed that both $CYP2C19^*2$ and $CYP2C19^*17$ were associated with increased survival. The pooled results of two studies for OS were OR=0.46 (95%CI=0.21-1.01, p=0.233). Conclusions: This meta-analysis suggests that the $CYP2C19^*2$ and $CYP2C19^*17$ genotypes are associated with increased survival in breast cancer patients using tamoxifen.

• The Journal of Korean Medicine
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• v.35 no.2
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• pp.47-59
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• 2014

Objectives: Most drug interactions are attributed to the inhibition or induction of the activity of cytochrome P450s (CYP450). Although the regulation of CYP450s by drugs has been widely reported, there have been few studies on influence of traditional herbal formulas on the drug-metabolizing enzymes. Because herbal formulas have been used traditionally to treat various diseases and because herb-drug interactions are crucial factors determining therapeutic efficacies, a systematic evaluation of the effects of herbal formulas is important. Methods: The effects of Galgeun-tang (GGT, gegen tang), Gumiganghwal-tang (GMGHT, jiuweiqianghuo tang), Insampaedok-san (ISPDS, renshenbaidu powder), Samsoeum (SSE, shensu drink), Socheongryong-tang (SCRT, xiaoqinglong-tang) and Sosiho-tang (SSHT, xiaochaihu tang) that are traditional herbal formulas used to treat common cold, on drug-metabolizing enzymes were evaluated through an in vitro CYP3A4, CYP2D6, CYP2C19 and CYP2E1 inhibition assay to assess its interaction potential with synthetic drugs. The inhibitory effects of herbal formulas were characterized with $IC_{50}$ values. Results: These six herbal formulas inhibited the activities of CYP3A4, 2C19, 2D6 and 2E1, in a concentration-dependent manner. Among the six herbal formulas, GGT critically inhibited CYP2C19, CYP2D6 and CYP2E1. GMGHT also inhibited CYP2D6 and CYP2E1 to a greater extent than the other CYP450 isozymes. Additionally, SSE and SSHT may change the effects of medicines that depend primarily on the CYP2C19 and CYP2E1 pathways. On the other hand, ISPDS and SCRT were not inhibited CYP3A4, CYP2C19, CYP2D6 and CYP2E1-mediated metabolism. Conclusions: These findings provide useful information regarding the safety and effectiveness of herbal formulas.

• Journal of Society of Preventive Korean Medicine
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• v.16 no.3
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• pp.129-137
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• 2012

Objective : Herb-drug interactions have become an important issue because of the consumption of herbal remedies has increased in the world. Yangguksanhaw-tang (Liang ge san huo-tang) and Taeumjowi-tang (Tai yin tiao wei-tang) are typical herbal formulas on Sasang constitution medicine (four-constitution medicine). This study was aimed at evaluating the effects of Yangguksanhaw-tang and Taeumjowi-tang on drug metabolizing enzymes, cytochrome P450 (CYP450) isozymes. Methods : Vivid$^{(R)}$ CYP450 Screening Kits were used to measure of CYP3A4, CYP2C19, CYP2D6 and CYP2E1 activities. This method is based on the use of fluorescent CYP450 substrates that are efficiently metabolized by specific CYP450 isozymes to yield a product with altered fluorescent properties. The percent inhibitions of CYP450s by herbal formulas were calculated. Results : Yangguksanhaw-tang inhibited CYP2C19 and CYP2E1 activities higher than that other CYP450 isozymes. The $IC_{50}$ values of CYP2C19 and CYP2E1 were 159.83 ${\mu}g/mL$ and 261.40 ${\mu}g/mL$, respectively. The CYP2E1 activity was inhibited ($IC_{50}=215.17{\mu}g/mL$) higher than that other CYP450 isozymes by Taeumjowi-tang. Conclusions : These results suggest that Yangguksanhaw-tang may inhibit the metabolism of co-administered drugs whose primary route of metabolism is via CYP2C19 or CYP2E1. Taeumjowi-tang could inhibit the metabolism of co-administered drugs, which are substrates for CYP2E1. Therefore, co-administration of the herbal formulas and other conventional drugs should be undertaken with care.

• Advances in Traditional Medicine
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• v.7 no.4
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• pp.357-362
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• 2007

Cytochrome P450 2C19 (CYP2C19) is a clinically important enzyme involved in the metabolism of therapeutic drugs, including (S)-mephenytoin, omeprazole, proguanil, and diazepam. Individuals are characterized as either extensive metabolizers (EM) or poor metabolizers (PM) on the basis of CYP2C19 enzyme activity. The PM phenotype occurs in 2-5% of Caucasians, but in 18-23% of Asians. To clarify the association between CYP2C19 polymorphisms and gastric cancer in Koreans, we investigated CYP2C19 genotypes ($CYP2C19^*1,\;{^*2},\;and\;^*3$) in 109 patients with gastric cancer and 211 controls. Normal ($CYP2C19^*1$) and defective alleles were detected with polymerase chain reaction/restriction enzyme analysis. CYP2C19 has three hereditary genotypes: homozygous EM, with high enzymatic activity; heterozygous EM, with moderate enzymatic activity; and PM, with no enzyme activity. We found that CYP2C19 heterozygous EM is more closely associated with gastric cancer than is homozygous EM. Because the CYP2C19 genotype varies in Koreans, a genotyping test is desirable to prevent gastropathy recurrence in patients before their doses of omeprazole are reduced during maintenance therapy.

• YAKHAK HOEJI
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• v.59 no.2
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• pp.49-54
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• 2015

In the present study we evaluated comparative herb-drug interaction potential of red ginseng total powder, ginsenoside Rg1, and Rb1 by inhibition of CYP isoforms including CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 using pooled human liver microsomes (HLMs). As measured by liquid chromatography-electrospray ionization tandem mass spectrometry, red ginseng total powder inhibited significantly activities of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and testosterone 6-beta hydroxylation by CYP3A4, but the $IC_{50}$ values were higher than $556{\mu}g/ml$. Activities of CYP2B6, CYP2C9, CYP2D6 and CYP3A4 were inhibited by ginsenoside Rb1. Also, activities of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and testosterone 6-beta hydroxylation by CYP3A4 were inhibited by ginsenoside Rg1. The $IC_{50}$ values of ginsenoside Rb1 and Rg1 were higher than $200{\mu}g/ml$. Based on $IC_{50}$ values against CYP isoforms, ginsenosides-drug interactions by CYP inhibition may be very low in clinical situations.

• Toxicological Research
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• v.17
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• pp.145-155
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• 2001

Cytochrome P4502C19 (CYP2C19) is one of human polymorphic xenobiotic-metabolizing enzymes. The enzyme has been reported to catalyze more than 70 substrates, involving more than 100 reactions. These include several classes of therapeutic agents (e.g. anti-microbial. cardiovascular, psycho-active, etc.), sex hormones and insecticides. Associations of the CYP2C19 genotype/phenotype with individual differences in drug efficacy (e.g. diazepam, omeprazole, proguanil) and toxicity (e.g. mephenytoin, barbiturates) have been documented by many investigators. At least 11 allelic variants of CYP2C19 gene were reported to date. Most of the mutant alleles found in the poor metabolizer (PM) led to the production of truncated and/or inactive proteins. Except for the exon 6, single-nucleotide mutations were reported in all nine exons of the gene. Genetic polymorphism of CYP2C19 shows marked interethnic variation with the population frequencies of PM phenotype ranging from 1∼2% up to more than 50%. The prevalence of CYP2C19 PM tends to be higher in Asian and certain Pacific Islanders than other race or ethnic specificity. Genotyping results of CYP2C19 also revealed that there are different proportions of individual mutant alleles among ethnic populations. This may, in part, explains the interethnic difference in the metabolism of certain drugs (i.e. diazepam), though they were from the same CYP2C19 phenotype. Recently, our research group has studied the genotype and phenotype of CYP2C19 and found that the PM frequency (7∼8%) in Thais is lower than other Asian populations. Molecular and clinical impacts of this finding warrant to further investigation.

• The Korean Journal of Physiology and Pharmacology
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• v.16 no.5
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• pp.339-342
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• 2012

Inter-individual pharmacokinetic variation of H2-receptor antagonist is related to genetic polymorphism of CYP2C19. We investigated the frequency of CYP2C19 genetic polymorphism and the treatment duration of cimetidine by CYP2C19 genotypes in functional dyspeptic patients without definite causes who were treated with cimetidine in Korea. One hundred subjects with functional dyspepsia participated in this study from March 1, 2010 to June 30, 2011. They were tested by upper gastrointestinal endoscopy and treated for their dyspepsia with cimetidine. The single nucleotide polymorphisms (SNPs) of CYP2C19 were genotyped using the Seeplex CYP2C19 ACE Genotyping system. There were no significant differences in the demographic, clinical, or laboratory findings among the CYP2C19 subgroups which are wild type homozygote (W/W), heterozygote (W/V), and variant homozygote (V/V). The frequencies of CYP2C19 subgroups were 33 (33%) in W/W, 49 (49%) in W/V, and 18 (18%) in V/V, respectively. The mean duration of cimetidine treatment (in weeks) was the shortest in the V/V among the CYP2C19 genotypes (W/W: $5.1{\pm}1.5$, W/V: $4.0{\pm}1.7$, V/V: $2.1{\pm}0.7$; p<0.001). This study can also act as a basis for further investigation to identify the underlying genetic, epigenetic, or environmental factors in CYP2C19 enzyme activity.

• Mass Spectrometry Letters
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• v.14 no.3
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• pp.116-119
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• 2023

Gynostemma pentaphyllum (Thunb.) Makino extract, a natural product with a history of traditional use, has gained attention for its potential health benefits. This study aimed to investigate its effects on key cytochrome P450 (CYP) enzymes using LC-MS/MS. Human liver microsomes and cDNA-expressed CYP2C8, CYP2C9, CYP2C19, and CYP3A4 supersomes were employed. Enzyme activity was assessed based on the formation of CYP-specific marker metabolites. The resulting data showed that the extract exhibited inhibitory effects on CYP2C8, CYP2C9, CYP2C19, and CYP3A4. Thus, G. pentaphyllum extract may influence the pharmacokinetics of drugs metabolized by CYP2C8, CYP2C9, CYP2C19, and CYP3A4. These findings emphasize the importance of considering potential herb-drug interactions when incorporating this extract into therapeutic regimens or dietary supplements.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.24
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• pp.10957-10960
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• 2015

Background: The CYP2C19 genotype has been found to be an important factor for peptic ulcer healing and H. pylori eradication, influencing the efficacy of proton pump inhibitors (PPIs) and the pathogenesis of gastric cancer. The aim of this study was to investigate clinical correlations of the CYP2C19 genotype in patients with gastritis, peptic ulcer disease (PUD), peptic ulcer bleeding (PUB) and gastric cancer in Thailand. Materials and Methods: Clinical information, endoscopic findings and H. pylori infection status of patients were assessed between May 2012 and November 2014 in Thammasat University Hospital, Thailand. Upper GI endoscopy was performed for all patients. Five milliliters of blood were collected for H. pylori serological diagnosis and CYP2C19 study. CYP2C19 genotypes were determined by polymerase chain reaction (PCR) and restriction fragment length polymorphism analysis (RFLP) and classified as rapid metabolizer (RM), intermediate metabolizer (IM) or poor metabolizer (PM). Results: A total of 202 patients were enrolled including 114 with gastritis, 36 with PUD, 50 with PUB and 2 with gastric cancer. Prevalence of CYP2C19 genotype was 82/202 (40.6%) in RM, 99/202 (49%) in IM and 21/202 (10.4%) in PM. Overall H. pylori infection was 138/202 patients (68.3%). H. pylori infection was demonstrated in 72% in RM genotype, 69.7% in IM genotype and 47.6% in PM genotype. Both gastric cancer patients had the IM genotype. In PUB patients, the prevalence of genotype RM (56%) was highest followed by IM (32%) and PM(12%). Furthermore, the prevalence of genotype RM in PUB was significantly greater than gastritis patients (56% vs 36%: p=0.016; OR=2.3, 95%CI=1.1-4.7). Conclusions: CYP2C19 genotype IM was the most common genotype whereas genotype RM was the most common in PUB patients. All gastric cancer patients had genotype IM. The CYP2C19 genotype RM might be play role in development of PUD and PUB. Further study in different population is necessary to verify clinical usefulness of CYP2C19 genotyping in development of these upper GI diseases.