Kolwankar Dhanashri, Vuppalanchi Raj, Ethell Brian, Jones David R, Wrighton Steven A, Hall Stephen D, Chalasani Naga
Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Clin Gastroenterol Hepatol. 2007 Mar;5(3):388-93. doi: 10.1016/j.cgh.2006.12.021.
BACKGROUND & AIMS: Comorbidities associated with nonalcoholic fatty liver often require therapy with medications (eg, statins) metabolized by cytochrome P-450 3A (CYP3A). There is significant interindividual variability in CYP3A expression. However, human studies that systematically examined the relationship between hepatic steatosis and hepatic CYP3A activity are lacking.
The relationship of hepatic CYP3A activity with several variables including hepatic steatosis, CYP3A4 protein content, CYP3A4 mRNA expression, CYP3A5 genotype, and its mRNA expression was investigated in human liver samples (n = 49). CYP3A activity was quantified from liver microsomes by using testosterone as a probe, and hepatic steatosis was defined to be present if >5% of hepatocytes had large globules of intracellular fat displacing the nucleus.
The mean +/- standard error hepatic CYP3A activity of the study group was 3156 +/- 2794 pmol x min(-1) x mg(-1) of protein, and it was not associated with age, gender, medicinal use, CYP3A5 or pregnane xenobiotic receptor mRNA expression, or CYP3A5 genotype. Twenty-four liver samples with steatosis had significantly lower hepatic CYP3A activity than 25 liver samples without steatosis (1978 +/- 299 vs 4287 +/- 659 pmol x min(-1) x mg(-1) of protein; P = .003). This difference persisted even after controlling for relevant covariates in the multivariate analysis (P = .04). However, CYP3A4 protein content was not different between the 2 groups (6 +/- 1.3 vs 8.5 +/- 2.2 pmol/mg protein; P = .3). There was a significant negative relationship between severity of steatosis and hepatic CYP3A activity (P = .01).
Hepatic steatosis is associated with decreased hepatic CYP3A activity in humans via post-translational mechanism. Further studies are needed to confirm our findings.
非酒精性脂肪性肝病相关的合并症常常需要使用经细胞色素P-450 3A（CYP3A）代谢的药物（如他汀类药物）进行治疗。CYP3A的表达存在显著的个体间差异。然而，缺乏系统研究肝脂肪变性与肝脏CYP3A活性之间关系的人体研究。
在49例人类肝脏样本中研究肝脏CYP3A活性与包括肝脂肪变性、CYP3A4蛋白含量、CYP3A4 mRNA表达、CYP3A5基因型及其mRNA表达在内的多个变量之间的关系。以睾酮作为探针，从肝微粒体中定量CYP3A活性，若>5%的肝细胞有大的细胞内脂肪球取代细胞核，则定义存在肝脂肪变性。
研究组肝脏CYP3A活性的平均值±标准误为3156±2794 pmol·min⁻¹·mg⁻¹蛋白，且与年龄、性别、药物使用、CYP3A5或孕烷异生素受体mRNA表达或CYP3A5基因型无关。24例有脂肪变性的肝脏样本的肝脏CYP3A活性显著低于25例无脂肪变性的肝脏样本（1978±299 vs 4287±659 pmol·min⁻¹·mg⁻¹蛋白；P = 0.003）。即使在多变量分析中对相关协变量进行校正后，这种差异仍然存在（P = 0.04）。然而，两组之间的CYP3A4蛋白含量没有差异（6±1.3 vs 8.5±2.2 pmol/mg蛋白；P = 0.3）。脂肪变性的严重程度与肝脏CYP3A活性之间存在显著的负相关（P = 0.01）。
在人类中，肝脂肪变性通过翻译后机制与肝脏CYP3A活性降低相关。需要进一步研究来证实我们的发现。
