Hepatic Cytochrome P450 Enzyme Alterations in Humans with Progressive Stages of Nonalcoholic Fatty Liver Disease
Hepatic Cytochrome P450 Enzyme Alterations in Humans with Progressive Stages of Nonalcoholic Fatty Liver Disease
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DOI：
10.1124/dmd.109.027466
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发表时间：
2009-10-01
影响因子：
3.9
通讯作者：
Cherrington, Nathan J.
中科院分区：
文献类型：
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作者：
Fisher, Craig D.;Lickteig, Andrew J.;Cherrington, Nathan J.
细胞色素P450（P450）酶家族CYP 1、CYP 2和CYP 3的成员负责约75%的所有临床相关药物的代谢。随着非酒精性脂肪性肝病（NAFLD）患病率的增加，这种疾病的患者可能代表了这些重要药物代谢酶改变的显著风险的新兴人群。本研究的目的是确定人类NALFD的三个进展阶段是否改变肝脏P450表达和活性。分析从诊断为正常的人肝样品（n = 20）、脂肪变性（n = 11）、非酒精性脂肪性肝炎（NASH）（脂肪肝）（n = 10）和NASH（不再脂肪）（n = 11）分离的微粒体的P450 mRNA、蛋白质和酶活性。微粒体CYP 1A 2、CYP 2D 6和CYP 2 E1 mRNA水平随着NAFLD进展而降低，而CYP 2A 6、CYP 2B 6和CYP 2C 9 mRNA表达增加。随着NAFLD进展，CYP 1A 2、CYP 2C 19、CYP 2D 6、CYP 2 E1和CYP 3A 4的微粒体蛋白表达趋于降低。同样，功能活性试验显示，随着NAFLD严重程度的增加，CYP 1A 2（p = 0.001）和CYP 2C 19（p = 0.05）酶活性呈下降趋势。相反，CYP 2A 6（p = 0.001）和CYP 2C 9（双氯芬酸，p = 0.0001;甲苯磺丁脲，p = 0.004）的活性随着NAFLD进展而显著增加。观察到促炎细胞因子肿瘤坏死因子α和白细胞介素1 β表达增加，可能是观察到的相应P450活性降低的原因。此外，NAFLD进展期间CYP 2C 9活性升高与NAFLD后期缺氧诱导因子1 α表达升高相关。这些结果表明，在NAFLD的进行性阶段，肝脏P450活性发生了显着的和新的变化。
Members of the cytochrome P450 (P450) enzyme families CYP1, CYP2, and CYP3 are responsible for the metabolism of approximately 75% of all clinically relevant drugs. With the increased prevalence of nonalcoholic fatty liver disease (NAFLD), it is likely that patients with this disease represent an emerging population at significant risk for alterations in these important drug-metabolizing enzymes. The purpose of this study was to determine whether three progressive stages of human NALFD alter hepatic P450 expression and activity. Microsomes isolated from human liver samples diagnosed as normal, n = 20; steatosis, n = 11; nonalcoholic steatohepatitis (NASH) (fatty liver), n = 10; and NASH (no longer fatty), n = 11 were analyzed for P450 mRNA, protein, and enzyme activity. Microsomal CYP1A2, CYP2D6, and CYP2E1 mRNA levels were decreased with NAFLD progression, whereas CYP2A6, CYP2B6, and CYP2C9 mRNA expression increased. Microsomal protein expression of CYP1A2, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 tended to decrease with NAFLD progression. Likewise, functional activity assays revealed decreasing trends in CYP1A2 (p = 0.001) and CYP2C19 (p = 0.05) enzymatic activity with increasing NAFLD severity. In contrast, activity of CYP2A6 (p = 0.001) and CYP2C9 (diclofenac, p = 0.0001; tolbutamide, p = 0.004) was significantly increased with NAFLD progression. Increased expression of proinflammatory cytokines tumor necrosis factor alpha and interleukin 1 beta was observed and may be responsible for observed decreases in respective P450 activity. Furthermore, elevated CYP2C9 activity during NAFLD progression correlated with elevated hypoxia-induced factor 1 alpha expression in the later stages of NAFLD. These results suggest that significant and novel changes occur in hepatic P450 activity during progressive stages of NAFLD.