Center for Engineering in Medicine and Surgery at Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, United States; Shriners Hospitals for Children, Boston, MA 02114, United States; Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093, United States.
Center for Engineering in Medicine and Surgery at Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, United States; Shriners Hospitals for Children, Boston, MA 02114, United States.
Biomed Pharmacother. 2022 Feb;146:112377. doi: 10.1016/j.biopha.2021.112377. Epub 2022 Jan 2.
Drug-drug-interactions (DDIs) occur when a drug alters the metabolic rate, efficacy, and toxicity of concurrently used drugs. While almost 1 in 4 adults now use at least 3 concurrent prescription drugs in the United States, the Non-alcoholic fatty liver disease (NAFLD) prevalence has also risen over 25%. The effect of NALFD on DDIs is largely unknown. NAFLD is characterized by lipid vesicle accumulation in the liver, which can progress to severe steatohepatitis (NASH), fibrosis, cirrhosis, and hepatic carcinoma. The CYP450 enzyme family dysregulation in NAFLD, which might already alter the efficacy and toxicity of drugs, has been partially characterized. Nevertheless, the drug-induced dysregulation of CYP450 enzymes has not been studied in the fatty liver. These changes in enzymatic inducibility during NAFLD, when taking concurrent drugs, could cause unexpected fatalities through inadvertent DDIs. We have, thus, developed an in vitro model to investigate the CYP450 transcriptional regulation in NAFLD. Specifically, we cultured primary human hepatocytes in a medium containing free fatty acids, high glucose, and insulin for seven days. These cultures displayed intracellular macro-steatosis after 5 days and cytokine secretion resembling NAFLD patients. We further verified the model's dysregulation in the transcription of key CYP450 enzymes. We then exposed the NAFLD model to the drug inducers rifampicin, Omeprazole, and Phenytoin as activators of transcription factors pregnane X receptor (PXR), aryl hydrocarbon receptor (AHR) and constitutive androstane receptor (CAR), respectively. In the NAFLD model, Omeprazole maintained an expected induction of CYP1A1, however Phenytoin and Rifampicin showed elevated induction of CYP2B6 and CYP2C9 compared to healthy cultures. We, thus, conclude that the fatty liver could cause aggravated drug-drug interactions in NAFLD or NASH patients related to CYP2B6 and CYP2C9 enzymes.
药物-药物相互作用（DDIs）是指当一种药物改变同时使用的其他药物的代谢率、疗效和毒性时发生的相互作用。虽然现在美国每 4 个成年人中就有近 1 个至少同时使用 3 种处方药，但非酒精性脂肪性肝病（NAFLD）的患病率也上升了 25%以上。NAFLD 对 DDI 的影响在很大程度上尚不清楚。NAFLD 的特征是肝脏中脂质囊泡的积累，这种积累可以进展为严重的脂肪性肝炎（NASH）、纤维化、肝硬化和肝细胞癌。NAFLD 中 CYP450 酶家族的失调已经部分得到了描述，这种失调可能已经改变了药物的疗效和毒性。然而，尚未在脂肪肝中研究药物诱导的 CYP450 酶失调。在 NAFLD 期间，当同时服用药物时，这些酶诱导能力的变化可能会导致意想不到的致命性 DDI。因此，我们开发了一种体外模型来研究 NAFLD 中 CYP450 的转录调控。具体来说，我们在含有游离脂肪酸、高葡萄糖和胰岛素的培养基中培养原代人肝细胞，培养 7 天。这些培养物在第 5 天显示出细胞内大脂滴，并分泌类似于 NAFLD 患者的细胞因子。我们进一步验证了该模型在关键 CYP450 酶转录中的失调。然后，我们将 NAFLD 模型暴露于药物诱导剂利福平、奥美拉唑和苯妥英钠中，分别作为转录因子孕烷 X 受体（PXR）、芳香烃受体（AHR）和组成型雄烷受体（CAR）的激活剂。在 NAFLD 模型中，奥美拉唑维持了 CYP1A1 的预期诱导，但苯妥英钠和利福平与健康培养物相比，显示 CYP2B6 和 CYP2C9 的诱导升高。因此，我们得出结论，脂肪肝可能导致与 CYP2B6 和 CYP2C9 酶相关的 NAFLD 或 NASH 患者的药物相互作用加剧。
