Genetic polymorphism of cytochrome P450 4F2, vitamin E level and histological response in adults and children with nonalcoholic fatty liver disease who participated in PIVENS and TONIC clinical trials.
Genetic polymorphism of cytochrome P450 4F2, vitamin E level and histological response in adults and children with nonalcoholic fatty liver disease who participated in PIVENS and TONIC clinical trials.
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DOI：
10.1371/journal.pone.0095366
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Chalasani N
中科院分区：
文献类型：
--
作者：
Athinarayanan S;Wei R;Zhang M;Bai S;Traber MG;Yates K;Cummings OW;Molleston J;Liu W;Chalasani N
维生素E改善了参与TONIC和PIVENS临床试验的NAFLD儿童和成人的肝脏组织学，但其疗效存在显著的个体间差异。细胞色素P450 4F2（CYP4F2）是代谢维生素E的主要酶，发现两种常见的遗传变异体（V433M，rs2108622和W12G，rs3093105）可改变其活性。我们研究了这两项试验中CYP4F2基因型、α-生育酚水平和组织学改善之间的关系。在TONIC（n = 155）和PIVENS（n = 213）DNA样本中对V433 M和W12 G变体进行基因分型。 研究了CYP4F2基因型、基线和第48周（w48）和第96周（w96）血浆α-生育酚水平与组织学终点（肝脏组织学总体改善和NASH消退）之间的关系。因此，在TONIC试验中，V433M基因型与基线血浆α-生育酚显著相关（p = 0.004），但在PIVENS中不相关。 在接受维生素E治疗的患者中，CYP4F2 V433M基因型与第48周时血浆α-生育酚水平显著降低相关（PIVENS组p = 0.003，TONIC组p = 0.026），但与第96周时无关。 在PIVENS试验中，w96 α-生育酚水平与NASH消退（p = 0.006）和总体组织学改善（p = 0.021）显著相关，但在TONIC试验中不相关。 在两项试验中，CYP4F2基因型与组织学终点之间无显著相关性。我们的研究表明，CYP4F2多态性在影响维生素E作为治疗剂的药代动力学中具有中等作用。此外，CYP4F2基因变异性与NAFLD中维生素E药代动力学之间可能存在年龄依赖性关系。
Vitamin E improved liver histology in children and adults with NAFLD who participated in TONIC and PIVENS clinical trials, but with significant inter-individual variability in its efficacy. Cytochrome P450 4F2 (CYP4F2) is the major enzyme metabolizing Vit E, with two common genetic variants (V433M, rs2108622 and W12G, rs3093105) found to alter its activity. We investigated the relationship between CYP4F2 genotypes, α-tocopherol levels and histological improvement in these two trials. V433M and W12G variants were genotyped in TONIC (n = 155) and PIVENS (n = 213) DNA samples. The relationships between CYP4F2 genotypes, plasma α-tocopherol levels at baseline and weeks 48 (w48) and 96 (w96) and histological end points (overall improvement in liver histology and resolution of NASH) were investigated. As a result, the V433M genotype was significantly associated with baseline plasma α-tocopherol in the TONIC trial (p = 0.004), but not in PIVENS. Among those receiving Vit E treatment, CYP4F2 V433M genotype was associated with significantly decreased plasma α-tocopherol levels at w48 (p = 0.003 for PIVENS and p = 0.026 for TONIC) but not at w96. The w96 α-tocopherol level was significantly associated with resolution of NASH (p = 0.006) and overall histology improvement (p = 0.021)in the PIVENS, but not in the TONIC trial. There was no significant association between CYP4F2 genotypes and histological end points in either trial. Our study suggested the a moderate role of CYP4F2 polymorphisms in affecting the pharmacokinetics of Vit E as a therapeutic agent. In addition, there may be age-dependent relationship between CYP4F2 genetic variability and Vit E pharmacokinetics in NAFLD.
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影响因子：
3.5
作者：
Major JM;Yu K;Wheeler W;Zhang H;Cornelis MC;Wright ME;Yeager M;Snyder K;Weinstein SJ;Mondul A;Eliassen H;Purdue M;Hazra A;McCarty CA;Hendrickson S;Virtamo J;Hunter D;Chanock S;Kraft P;Albanes D
通讯作者：
Albanes D
功能性细胞色素 P4504F2 单倍型与尿 20-HETE 和高血压的关联
影响因子：
13.6
作者：
Liu, Hong;Zhao, Yanyan;Lu, Jingyu
通讯作者：
Lu, Jingyu
影响因子：
4.3
作者：
Lodge, JK
通讯作者：
Lodge, JK
影响因子：
8.3
作者：
Fava, Cristiano;Montagnana, Martina;Melander, Olle
通讯作者：
Melander, Olle
影响因子：
5.2
作者：
Curley, Christine R.;Monsuur, Alienke J.;Wijmenga, Cisca
通讯作者：
Wijmenga, Cisca