Evaluation of Human Hepatocyte Drug Metabolism Carrying High-Risk or Protection-Associated Liver Disease Genetic Variants.
Evaluation of Human Hepatocyte Drug Metabolism Carrying High-Risk or Protection-Associated Liver Disease Genetic Variants.
复制标题
DOI：
10.3390/ijms241713406
复制
发表时间：
2023-08-29
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
代谢功能障碍相关性脂肪性肝病(MASLD)在美国影响着3000万人，预计到2030年将超过1亿人，这给医疗体系带来了巨大的财务压力。尽管MASLD具有公共卫生意义和经济负担，但目前还没有FDA批准的治疗方法。了解点突变、肝酶和MASLD之间的联系对于了解健康或疾病个体的药物毒性很重要。通过全基因组关联研究，多个基因变异与MASLD的易感性有关，增加或预防MASLD的风险，如PNPLA3 rs738409、MBOAT7 rs641738、GCKR rs780094、HSD17B13 rs72613567和MTARC1 rs2642438。由于遗传变异对人肝细胞药物代谢细胞色素P450(CYP)酶水平的影响尚未得到深入研究，本研究旨在对人肝细胞中部分I期和II期肝酶的代谢功能进行分析。为此，新鲜分离的原代肝细胞取自健康供者(n=126)，并进行了液质联用(LC-MS)。对于队列，参与者被分为五个基因多态性的次要纯合子和非次要纯合子(主要纯合子+杂合子)。对于I期肝酶，我们发现携带MBOAT 7的人肝细胞中的细胞色素P450 1A2的活性(p=0.011)和携带PNPLA3的人肝细胞中的细胞色素P 2 C8的活性(p=0.004)有显著差异。还观察到携带HSD17B13(p=0.001)轻微纯合子的人肝细胞中细胞色素P450酶2 C9的活性显著低于非轻微纯合子。在携带PNPLA3 rs738409、MBOAT7 rs641738、GCKR rs780094、HSD17B13 rs72613567和MTARC1rs2642438基因变异的人肝细胞中，没有观察到CYP2E1、CYP2C8、CYP2D6、CYP2E1、CYP3A4、ECOD、FMO、MAO、AO和CES2的活性以及任何II相肝酶活性的显著差异。这些发现为基因变异对健康人肝细胞药物代谢细胞色素P450(CYP)酶的影响提供了初步评估，这可能有助于未来的药物发现研究。
Metabolic-dysfunction-associated steatotic liver disease (MASLD), which affects 30 million people in the US and is anticipated to reach over 100 million by 2030, places a significant financial strain on the healthcare system. There is presently no FDA-approved treatment for MASLD despite its public health significance and financial burden. Understanding the connection between point mutations, liver enzymes, and MASLD is important for comprehending drug toxicity in healthy or diseased individuals. Multiple genetic variations have been linked to MASLD susceptibility through genome-wide association studies (GWAS), either increasing MASLD risk or protecting against it, such as PNPLA3 rs738409, MBOAT7 rs641738, GCKR rs780094, HSD17B13 rs72613567, and MTARC1 rs2642438. As the impact of genetic variants on the levels of drug-metabolizing cytochrome P450 (CYP) enzymes in human hepatocytes has not been thoroughly investigated, this study aims to describe the analysis of metabolic functions for selected phase I and phase II liver enzymes in human hepatocytes. For this purpose, fresh isolated primary hepatocytes were obtained from healthy liver donors (n = 126), and liquid chromatography–mass spectrometry (LC–MS) was performed. For the cohorts, participants were classified into minor homozygotes and nonminor homozygotes (major homozygotes + heterozygotes) for five gene polymorphisms. For phase I liver enzymes, we found a significant difference in the activity of CYP1A2 in human hepatocytes carrying MBOAT7 (p = 0.011) and of CYP2C8 in human hepatocytes carrying PNPLA3 (p = 0.004). It was also observed that the activity of CYP2C9 was significantly lower in human hepatocytes carrying HSD17B13 (p = 0.001) minor homozygous compared to nonminor homozygous. No significant difference in activity of CYP2E1, CYP2C8, CYP2D6, CYP2E1, CYP3A4, ECOD, FMO, MAO, AO, and CES2 and in any of the phase II liver enzymes between human hepatocytes carrying genetic variants for PNPLA3 rs738409, MBOAT7 rs641738, GCKR rs780094, HSD17B13 rs72613567, and MTARC1 rs2642438 were observed. These findings offer a preliminary assessment of the influence of genetic variations on drug-metabolizing cytochrome P450 (CYP) enzymes in healthy human hepatocytes, which may be useful for future drug discovery investigations.
登录
查看更多内容
DOI：
10.1002/hep.30350
发表时间：
2019-04
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Ma Y;Belyaeva OV;Brown PM;Fujita K;Valles K;Karki S;de Boer YS;Koh C;Chen Y;Du X;Handelman SK;Chen V;Speliotes EK;Nestlerode C;Thomas E;Kleiner DE;Zmuda JM;Sanyal AJ;(for the Nonalcoholic Steatohepatitis Clinical Research Network);Kedishvili NY;Liang TJ;Rotman Y
通讯作者：
Rotman Y
DOI：
10.1097/00008571-200110000-00006
发表时间：
2001-10-01
期刊：
PHARMACOGENETICS
影响因子：
--
作者：
Dai, D;Zeldin, DC;Goldstein, JA
通讯作者：
Goldstein, JA
影响因子：
25.7
作者：
Ioannou, George N.
通讯作者：
Ioannou, George N.
影响因子：
13.5
作者：
Rotman, Yaron;Koh, Christopher;Zmuda, Joseph M.;Kleiner, David E.;Liang, T. Jake
通讯作者：
Liang, T. Jake
HSD17B13遗传变体是肝功能障碍的保护因子吗？未来的观点是潜在的治疗靶点。
影响因子：
--
作者：
Motomura T;Amirneni S;Diaz-Aragon R;Faccioli LAP;Malizio MR;Coard MC;Kocas-Kilicarslan ZN;Frau C;Haep N;Ostrowska A;Florentino RM;Soto-Gutierrez A
通讯作者：
Soto-Gutierrez A