Ethnic differences in allelic frequency of two flavin-containing monooxygenase 3 (FMO3) polymorphisms: linkage and effects on in vivo and in vitro FMO activities.
Ethnic differences in allelic frequency of two flavin-containing monooxygenase 3 (FMO3) polymorphisms: linkage and effects on in vivo and in vitro FMO activities.
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两种含黄素单加氧酶 3 (FMO3) 多态性的等位基因频率的种族差异：关联及其对体内和体外 FMO 活性的影响。
DOI：
10.1097/00008571-200201000-00011
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发表时间：
2002
期刊：
影响因子：
--
通讯作者：
Cha,Young-Nam
中科院分区：
文献类型：
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作者：
Park,Chang-Shin;Kang,Ju-Hee;Chung,Woon-Gye;Yi,Hyun-Gyu;Pie,Jae-Eun;Park,Dong-Kyun;Hines,RN;McCarver,DG;Cha,Young-Nam
与含血红素的细胞色素P450依赖性单加氧酶一起，含黄素的单加氧酶（FMO：EC. 1.14. 13.8）在氧化许多亲核的含氮、硫和磷的药物、农药和植物产品中起主要作用[1]。在哺乳动物中鉴定的五种已知FMO同种型中，FMO 3是成人肝脏中存在的主要酶。许多药物代谢酶活性的受试者间变异性部分由其各自基因中的单核苷酸多态性决定。种族群体之间等位基因频率的差异也有助于异生物质代谢的变异性。FMO 3中几个导致功能丧失的单核苷酸突变已被鉴定，这些突变代表了导致罕见遗传疾病三甲基氨基尿症（TMAU）或鱼味综合征的罕见等位基因[2±5]。然而，在不同人群中观察到的FMO 3依赖性肝脏药物代谢能力的实质性差异不能全部归因于这些罕见等位基因中的任何一个。相反，更常见的突变产生的改变，但功能FMO 3必须负责，因此，是相当大的interests.In以前的研究中，我们确定了两个FMO 3序列变异，不使酶（Glu 158 Lys和Glu 308 Gly），并发生在韩国人口中的相对较高的频率（约18%的两个突变等位基因）[6，7]。通过雷尼替丁N-氧化测定，这两个等位基因中任一个的杂合子或纯合子志愿者体内FMO活性正常，但不是两个都正常。然而，两个等位基因都是杂合子或纯合子的志愿者，
Together with the heme-containing cytochrome P450-dependent monooxygenases, the flavin-containing monooxygenases (FMOs: EC. 1.14. 13.8) play a major role in oxidizing many nucleophilic nitrogen-, sulfurand phosphorus-containing drugs, pesticides and plant products [1]. Among the five known FMO isoforms identified in mammals, FMO3 is the major enzyme present in adult human liver. Inter-subject variability in the activity of many drug-metabolizing enzymes is determined in part by single nucleotide polymorphisms in their respective genes. Differences in allelic frequencies among ethnic groups also contribute to variability in xenobiotic metabolism. Several single nucleotide mutations in FMO3 that cause loss-of-function have been identified and these represent rare alleles responsible for the rare genetic disease namedtrimethylaminuria (TMAU)'orfish-odor syndrome'[2±5]. However, the substantial differences in FMO3-dependent hepatic drug metabolism capacity observed within or among different populations cannot all be attributed to any one of these rare alleles. Rather, more common mutations producing the altered, but functional FMO3 must be responsible and as such, are of considerable interest.In previous studies, we identified two FMO3 sequence variants that do not inactivate the enzyme (Glu158Lys and Glu308Gly) and that occur at a relatively high frequency within the Korean population (about 18% for both mutant alleles)[6, 7]. Heterozygous or homozygous volunteers for either one, but not both of these two alleles had normal in-vivo FMO activity as measured by ranitidine N-oxidation. However, the volunteers who were heterozygous or homozygous for both alleles