Oxidation of R- and S-omeprazole stereoselectively mediated by liver microsomal cytochrome P450 2C19 enzymes from cynomolgus monkeys and common marmosets.
Oxidation of R- and S-omeprazole stereoselectively mediated by liver microsomal cytochrome P450 2C19 enzymes from cynomolgus monkeys and common marmosets.
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由食蟹猴和普通狨猴的肝微粒体细胞色素 P450 2C19 酶立体选择性介导的 R-和 S-奥美拉唑的氧化。
DOI：
10.1016/j.bcp.2016.09.010
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
H.
中科院分区：
文献类型：
--
作者：
Uehara;S.;Kawano;M.;Murayama;N.;Uno;Y.;Utoh;M.;Inoue;T.;Sasaki;E.;and Yamazaki;H.
外消旋奥美拉唑已被用于临床治疗胃酸相关性疾病，在临床前研究中也被用作典型的人类细胞色素P450(P450)2C19探针底物。S-奥美拉唑已被开发为单一对映体药物，已被报道与人类P450 2C19表型的多态无关。本文研究了实验动物(包括非人灵长类动物和人类)的肝微粒体对R-和奥美拉唑立体选择性氧化的5-羟化和亚硫氧化活性。来自人、食蟹猴和小鼠的肝微粒体优先介导R-奥美拉唑5-羟化，而来自绒猴、小型猪、狗和大鼠的肝微粒体优先介导S-奥美拉唑5-羟化。重组人P450 2C19 INR-奥美拉唑5-羟化反应、食蟹猴P450 2C19 R-和奥美拉唑5-羟化反应以及绒猴P450 2C19 INR-奥美拉唑5-羟化反应均表现出较高的催化活性。另一方面，人、食蟹猴和绒猴P450 3A酶优先介导S-奥美拉唑亚磺化。相关和动力学分析表明，食蟹猴和猴肝微粒体P450 2C19酶的多态分别对5-羟化和奥美拉唑5-羟化有很高的亲和力，食蟹猴和猴肝微粒体P450 3A4对5-羟化和亚磺化有很高的亲和力。食蟹猴和猴肝微粒体P450-Omerazole 5-羟化活性在野生型、杂合型和纯合型动物之间有显著差异。Ile469Thr)]。本研究的结果显示食蟹猴和绒猴P450 2C19依赖的奥美拉唑氧化活性具有多态，其个体差异与人类相似。
Racemic omeprazole has been used for clinically treating gastric acid-related diseases and also as a typical human cytochrome P450 (P450) 2C19 probe substrate in preclinical studies.S-Omeprazole has been developed as a single enantiomer medicine, which has been reported not to be associated with polymorphic human P450 2C19 phenotypes. In this study, 5-hydroxylation and sulfoxidation activities, with respect to stereoselectiveR- andS-omeprazole oxidations by liver microsomes from experimental animals including non-human primates and humans, were investigatedin vitro. Liver microsomes from humans, cynomolgus monkeys, and mice preferentially mediatedR-omeprazole 5-hydroxylations, however those from marmosets, minipigs, dogs, and rats preferentially mediatedS-omeprazole 5-hydroxylations. High catalytic activities were observed for recombinant human P450 2C19 inR-omeprazole 5-hydroxlations, cynomolgus monkey P450 2C19 in bothR- andS-omeprazole 5-hydroxlations, and marmoset P450 2C19 inS-omeprazole 5-hydroxlations. On the other hand, human, cynomolgus monkey, and marmoset P450 3A enzymes preferentially mediatedS-omeprazole sulfoxidations. Correlation and kinetic analyses revealed a high affinity of polymorphic cynomolgus monkey and marmoset liver microsomal P450 2C19 enzymes with respect toR- andS-omeprazole 5-hydroxylations, respectively, and a high capacity of cynomolgus monkey and marmoset liver microsomal P450 3A4 for omeprazole 5-hydroxylations and sulfoxidations.R-andS-omeprazole 5-hydroxylation activities in cynomolgus monkey and marmoset liver microsomes were significantly different among wild-type, heterozygous, and homozygous animals genotyped for cynomolgus monkeyP450 2C19p.[(Phe100Asn; Ala103Val; Ile112Leu)] and for marmosetP450 2C19p.[(Phe7Leu; Ser254Leu; Ile469Thr)], respectively.The results of this study demonstrate polymorphic cynomolgus monkey and marmoset P450 2C19-dependent omeprazole oxidation activities with individual variations similar to humans.