Genetic Variations of CYP2C9 in 724 Japanese Individuals and Their Impact on the Antihypertensive Effects of Losartan

Yin, Tong; Maekawa, Keiko; Kamide, Kei; Saito, Yoshiro; Hanada, Hironori; Miyashita, Kotaro; Kokubo, Yoshihiro; Akaiwa, Yasuhisa; Otsubo, Ryoichi; Nagatsuka, Kazuyuki; Otsuki, Toshiho; Horio, Takeshi; Takiuchi, Shin; Kawano, Yuhei; Minematsu, Kazuo; Naritomi, Hiroaki; Tomoike, Hitonobu; Sawada, Jun‐ichi; Miyata, Toshiyuki

doi:10.1291/hypres.31.1549

Cited by 65 publications

(58 citation statements)

References 41 publications

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“…Genetic polymorphisms of CYP2C9 include more than 34 alleles (41). Alleles CYP2C9*2, *3, *4,*5, and *30 have aminoacid replacement, and have been reported to reduce in vitro (107,108) and/or in vivo catalityc activities (108,109,110).…”

Section: Cyp2c9mentioning

confidence: 99%

Genetic Polymorphism of Metabolic Enzymes P450 (CYP) as a Susceptibility Factor for Drug Response, Toxicity, and Cancer Risk

Božina¹,

Bradamante

Lovrić

2009

Archives of Industrial Hygiene and Toxicology

165

111

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The polymorphic P450 (CYP) enzyme superfamily is the most important system involved in the biotransformation of many endogenous and exogenous substances including drugs, toxins, and carcinogens. Genotyping for CYP polymorphisms provides important genetic information that help to understand the effects of xenobiotics on human body. For drug metabolism, the most important polymorphisms are those of the genes coding for CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5, which can result in therapeutic failure or severe adverse reactions. Genes coding for CYP1A1, CYP1A2, CYP1B1, and CYP2E1 are among the most responsible for the biotransformation of chemicals, especially for the metabolic activation of pre-carcinogens. There is evidence of association between gene polymorphism and cancer susceptibility. Pathways of carcinogen metabolism are complex, and are mediated by activities of multiple genes, while single genes have a limited impact on cancer risk. Multigenic approach in addition to environmental determinants in large sample studies is crucial for a reliable evaluation of any moderate gene effect. This article brings a review of current knowledge on the relations between the polymorphisms of some CYPs and drug activity/toxicity and cancer risk.

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Section: Cyp2c9mentioning

confidence: 99%

Genetic Polymorphism of Metabolic Enzymes P450 (CYP) as a Susceptibility Factor for Drug Response, Toxicity, and Cancer Risk

Božina¹,

Bradamante

Lovrić

2009

Archives of Industrial Hygiene and Toxicology

165

111

View full text Add to dashboard Cite

show abstract

“…The data showed a serious impact on CYP2C9*34 enzymatic activity, whereas in the study of Yin et al (2008), a slight diminution in intrinsic clearance (6%) was observed for the CYP2C9*34 (Arg 335 Gln) protein with slightly decreased Km and Vmax values in in vitro investigation. CYP2C9*40, CYP2C9*41, CYP2C9*42, CYP2C9*45, CYP2C9*46, and CYP2C9*48 were the six novel variants found in our previous study (Dai et al, 2014b).…”

Section: Downloaded Frommentioning

confidence: 78%

In Vitro and In Vivo Characterization of 13 CYP2C9 Allelic Variants Found in Chinese Han Population

Pan

Wang

et al. 2015

Drug Metab Dispos

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Our previous study detected totally 35 CYP2C9 allelic variants in 2127 Chinese subjects, of whom 21 novel alleles were reported for the first time in Chinese populations. The aim of the present study was to characterize the 13 CYP2C9 allelic variants both in vitro and in vivo. Different types of CYP2C9 variants were highly expressed in COS-7 cells, and 50 mM tolbutamide was added as the probing substrate to evaluate their metabolic abilities in vitro. Subsequently, the concentrations of tolbutamide and its metabolite in the plasma and urine within individuals with different types of genotypes were determined by HPLC to evaluate the catalytic activity of the 13 mutant CYP2C9 proteins in vivo. Our results showed that compared with *1/*1 wild-type subjects, subjects with *1/*40 genotype showed increased oral clearance (CL/F), whereas individuals with

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“…We focused on polymorphisms in the gene that codes for CYP2C9, which is a partial metabolite of the ARB, losartan. 32 We resequenced CYP2C9 in 724 Japanese individuals, including 39 hypertensive patients receiving losartan treatment. Of the two novel missense mutations identified, the Arg132Gln variant showed a fivefold lower intrinsic clearance of diclofenac metabolized by CYP2C9 when expressed in a baculovirusinsect cell system, whereas the Arg335Gln variant had no substantial effect on clearance.…”

Section: Current Trends In Pharmacogenetic/ Pharmacogenomic Studies Omentioning

confidence: 99%

“…CYP2C9*30 might be associated with a diminished response to the antihypertensive effects of losartan. 32,33 These rare mutations related to the effects of antihypertensive drugs should be clarified for all antihypertensive drugs.…”

Section: Current Trends In Pharmacogenetic/ Pharmacogenomic Studies Omentioning

confidence: 99%

Pharmacogenomic approaches to study the effects of antihypertensive drugs

2012

Self Cite

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Pharmacogenomic studies aim to clarify the role of various genes and their variations in relation to the effects of antihypertensive drugs to establish a personalized pharmacotherapeutic treatment based on a patient's genetic background. Until recently, there have been numerous pharmacogenetic/pharmacogenomic studies on antihypertensive drugs using candidate genes, but only a few genome-wide approaches have been completed. In this review article, we discuss current trends and future directions of pharmacogenomic studies on antihypertensive drugs. Hypertension Research (2012) 35, 796-799; doi:10.1038/hr.2012; published online 28 June 2012 Keywords: antihypertensive drugs; candidate genes; GWAS; pharmacogenomics; tailored medicine INTRODUCTION Hypertension is the most common risk factor for atherosclerotic cardiovascular diseases, and its morbidity is greater than 50% in subjects aged 65 years and older in Japan and most Western countries. In Japan, the number of patients with hypertension is estimated to be greater than 40 million. 1 Hypertension is a multifactorial disease in which genetic and environmental factors are closely related. Specifically, genetic factors can influence blood pressure elevation by 30-50%. 2 Thus, over the last decade, many genetic studies have aimed to clarify the causal genes of hypertension, as reviewed previously. 3 Genetic research on hypertension started using the candidate gene approach by investigating renin-angiotensin system (RAS)-related genes. [4][5][6] Recently, several large-scale genome-wide association studies (GWASs) for hypertension 7-9 were performed, and B50 single nucleotide polymorphisms (SNPs) were identified as possible causal genes.The goal of genetic studies on hypertension is mainly to clarify the causal genes of hypertension and the mechanisms of blood pressure elevation. Consequently, these approaches may lead to the production of novel antihypertensive drugs. Another important aim is to establish personalized pharmacotherapy based on genetic information. These were the two main aims of the Japanese Millennium Project for Hypertension. 10 As mentioned, the first aim may be reasonably addressed by large-scale GWAS, but the second aim has not yet been examined in the field of hypertension research.Recent studies indicate that the heterogeneity of patients' responses to antihypertensive treatment is, at least in part, genetically determined. 11 This finding underscores the role of pharmacogenetic/ pharmacogenomic research in identifying either functional genetic variations or those variations inherited by linkage disequili-

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Genetic Variations of CYP2C9 in 724 Japanese Individuals and Their Impact on the Antihypertensive Effects of Losartan

Cited by 65 publications

References 41 publications

Genetic Polymorphism of Metabolic Enzymes P450 (CYP) as a Susceptibility Factor for Drug Response, Toxicity, and Cancer Risk

Genetic Polymorphism of Metabolic Enzymes P450 (CYP) as a Susceptibility Factor for Drug Response, Toxicity, and Cancer Risk

In Vitro and In Vivo Characterization of 13 CYP2C9 Allelic Variants Found in Chinese Han Population

Pharmacogenomic approaches to study the effects of antihypertensive drugs

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