Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands (L.M.J., C.H., D.-J.B., M.H., N.J.P, M.L.M); Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands (J.J.S); Centre for Human Drug Research, Leiden, Netherlands (R.R.); Division of Biotherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands (R.R.); Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands (R.R.).
Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands (L.M.J., C.H., D.-J.B., M.H., N.J.P, M.L.M); Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands (J.J.S); Centre for Human Drug Research, Leiden, Netherlands (R.R.); Division of Biotherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands (R.R.); Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands (R.R.)
Drug Metab Dispos. 2024 Nov 15;52(12):1429-1437. doi: 10.1124/dmd.124.001867.
Compromised hepatic drug metabolism in response to proinflammatory cytokine release is primarily attributed to downregulation of cytochrome P450 (CYP) enzymes. However, whether inflammation also affects other phase I and phase II drug metabolizing enzymes (DMEs), such as the flavin monooxygenases (FMOs), carboxylesterases (CESs), and UDP glucuronosyltransferases (UGTs), remains unclear. This study aimed to decipher the impact of physiologically relevant concentrations of proinflammatory cytokines on expression and activity of phase I and phase II enzymes, to establish a hierarchy of their sensitivity as compared with the CYPs. Hereto, HepaRG cells were exposed to interleukin-6 and interleukin-1 to measure alterations in DME gene expression (24 h) and activity (72 h). Sensitivity of DMEs toward proinflammatory cytokines was evaluated by determining IC (potency) and I (maximal inhibition) values from the concentration-response curves. Proinflammatory cytokine treatment led to nearly complete downregulation of (∼98%) but was generally less efficacious at reducing gene expression of the non-CYP DME families. Importantly, FMO, CES, and UGT family members were less sensitive toward interleukin-6 induced inhibition in terms of potency, with IC values that were 4.3- to 7.4-fold higher than Similarly, 18- to 31-fold more interleukin-1 was required to achieve 50% of the maximal downregulation of expression. The differential sensitivity persisted at enzyme activity level, highlighting that alterations in DME gene expression during inflammation are predictive for subsequent alterations in enzyme activity. In conclusion, this study has shown that FMOs, CESs, and UGTs enzymes are less impacted by IL-6 and IL-1 treatment as compared with CYP enzymes. SIGNIFICANCE STATEMENT: While the impact of proinflammatory cytokines on CYP expression is well established, their effects on non-CYP phase I and phase II drug metabolism remains underexplored, particularly regarding alterations in drug metabolizing enzyme (DME) activity. This study provides a quantitative understanding of the sensitivity differences to inflammation between DME family members, suggesting that non-CYP DMEs may become more important for the metabolism of drugs during inflammatory conditions due to their lower sensitivity as compared with the CYPs.
细胞色素 P450（CYP）酶下调是炎症反应导致药物代谢受损的主要原因。然而，炎症是否也会影响其他 I 相和 II 相药物代谢酶（DME），如黄素单加氧酶（FMO）、羧酸酯酶（CES）和 UDP 葡糖醛酸基转移酶（UGT），目前尚不清楚。本研究旨在阐明生理相关浓度的促炎细胞因子对 I 相和 II 相酶表达和活性的影响，并确定与 CYP 相比它们的敏感性顺序。为此，用白细胞介素 6 和白细胞介素 1 处理 HepaRG 细胞，以测量 DME 基因表达（24 h）和活性（72 h）的变化。通过从浓度反应曲线确定 IC（效力）和 I（最大抑制）值来评估 DME 对促炎细胞因子的敏感性。促炎细胞因子处理导致几乎完全下调（~98%），但通常在降低非 CYP DME 家族的基因表达方面效果较差。重要的是，FMO、CES 和 UGT 家族成员对白细胞介素 6 诱导的抑制作用的敏感性较低，其效力的 IC 值比 CYP 高 4.3-7.4 倍。同样，需要 18-31 倍更多的白细胞介素 1 才能达到 CYP 表达最大下调的 50%。在酶活性水平上，这种差异仍然存在，这表明炎症期间 DME 基因表达的改变可预测随后的酶活性改变。总之，本研究表明，与 CYP 酶相比，FMO、CES 和 UGT 酶受白细胞介素 6 和白细胞介素 1 治疗的影响较小。
虽然促炎细胞因子对 CYP 表达的影响已得到充分证实，但它们对非 CYP I 相和 II 相药物代谢的影响仍未得到充分探索，特别是关于药物代谢酶（DME）活性的改变。本研究提供了对 DME 家族成员对炎症反应敏感性差异的定量理解，表明与 CYP 相比，由于非 CYP DME 的敏感性较低，它们在炎症条件下可能对药物代谢变得更加重要。
