Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, China.
J Pharmacol Sci. 2014;124(4):433-44. doi: 10.1254/jphs.13212fp.
Accumulating evidences have shown that diabetes upregulated the function and expression of CYP3A4, but the mechanism remained unclear. In this study, HepG2 cells were incubated with serum from diabetic rats induced by streptozotocin, and the activity of CYP3A4 was measured by substrate metabolism. Results showed that incubation with diabetic serum significantly induced CYP3A4 activity in HepG2 cells. To identify the specific factors contributing to the regulation, the abnormally altered components in diabetic serum, including glucose, insulin, cholesterol, and free fatty acids were screened. It was found that only fatty acids concentration-dependently up-regulated CYP3A4 activity, and the induction by fatty acids was further confirmed in Fa2N-4 cells. Data from western blotting and QT-PCR showed that induction of CYP3A4 activity was associated with up-regulation of CYP3A4 protein and mRNA levels. In addition, effects of pharmacological inhibitors on fatty acid-induced CYP3A4 activity were studied. The results indicated that the induction of CYP3A4 activity by oleic acid may be partly via AMPK-, PKC-, and NF-κB-dependent pathways, whereas that by palmitic acid was possibly associated with the PKC-dependent pathway. In conclusion, the increased levels of fatty acids may be one of the reasons leading to the elevated function and expression of CYP3A4 under diabetic conditions.
越来越多的证据表明，糖尿病会上调 CYP3A4 的功能和表达，但具体机制尚不清楚。在这项研究中，用链脲佐菌素诱导的糖尿病大鼠血清孵育 HepG2 细胞，并通过底物代谢来测量 CYP3A4 的活性。结果表明，用糖尿病血清孵育可显著诱导 HepG2 细胞中 CYP3A4 的活性。为了确定起调节作用的特定因素，筛选了糖尿病血清中异常改变的成分，包括葡萄糖、胰岛素、胆固醇和游离脂肪酸。结果发现，只有脂肪酸浓度依赖性地上调 CYP3A4 活性，并且在 Fa2N-4 细胞中进一步证实了脂肪酸的诱导作用。Western blot 和 QT-PCR 数据表明，CYP3A4 活性的诱导与 CYP3A4 蛋白和 mRNA 水平的上调有关。此外，还研究了药理学抑制剂对脂肪酸诱导的 CYP3A4 活性的影响。结果表明，油酸诱导 CYP3A4 活性可能部分通过 AMPK、PKC 和 NF-κB 依赖性途径，而棕榈酸诱导可能与 PKC 依赖性途径有关。总之，在糖尿病条件下，脂肪酸水平的升高可能是 CYP3A4 功能和表达升高的原因之一。
