Department of Pharmacy, Shinshu University Hospital, 3-1-1 Asahi, Matsumoto, 390-8621, Japan; Department of Biochemical Pharmacology and Toxicology, Graduate School of Medicine, Shinshu University, 3-1-1 Asahi, Matsumoto, 390-8621, Japan.
School of Medicine, Shinshu University, 3-1-1 Asahi, Matsumoto, 390-8621, Japan.
Chem Biol Interact. 2023 Sep 1;382:110644. doi: 10.1016/j.cbi.2023.110644. Epub 2023 Jul 25.
Cytochrome P450 4A11 (CYP4A11) has many endogenous and exogenous compounds containing a carboxyl group in their structure as substrates. If drugs with this characteristic potently attenuate the catalytic function of CYP4A11, drug-drug interactions may occur. Acidic non-steroidal anti-inflammatory drugs (NSAIDs) possess a carboxylic acid in their structure. However, it remains unclear whether these drugs inhibit CYP4A11 activity. The present study examined the inhibitory effects of acidic NSAIDs on CYP4A11 activity using human liver microsomes (HLMs) and recombinant CYP4A11. Sulindac sulfide, ibuprofen, and flurbiprofen effectively decreased the luciferin-4A O-demethylase activity of HLMs and recombinant CYP4A11 (inhibition rates of 30-96% at an inhibitor concentration of 100 μM), while salicylic acid, aspirin, diclofenac, mefenamic acid, indomethacin, etodolac, ketoprofen, loxoprofen, S-naproxen, pranoprofen, zaltoprofen, and oxaprozin exhibited weaker inhibitory activity (inhibition rates up to 23%). Among the drugs tested, sulindac sulfide was the most potent inhibitor of CYP4A11 activity. A kinetic analysis of the inhibition of CYP4A11 by sulindac sulfide revealed mixed-type inhibition for HLMs (K = 3.38 μM) and recombinant CYP4A11 (K = 4.19 μM). Sulindac sulfide is a pharmacologically active metabolite of sulindac (sulfoxide form), which is also oxidized to sulindac sulfone. To elucidate the role of a sulfur atom of sulindac sulfide in the inhibition of CYP4A11, the inhibitory effects of sulindac sulfide and its oxidized forms on CYP4A11 activity were examined. The potency of inhibition against HLMs was greater in the order of sulindac sulfide, sulindac, and sulindac sulfone; IC values were 6.16, 52.7, and 71.6 μM, respectively. The present results indicate that sulindac sulfide is a potent inhibitor of CYP4A11. These results and the molecular modeling of CYP4A11 with sulindac sulfide and its oxidized forms suggest that a sulfur atom of sulindac sulfide as well as its carboxylic acid play important roles in the inhibition of CYP4A11.
细胞色素 P450 4A11（CYP4A11）是许多内源性和外源性化合物的酶，这些化合物的结构中都含有一个羧基作为底物。如果具有这种特征的药物能有效减弱 CYP4A11 的催化功能，就可能发生药物-药物相互作用。酸性非甾体抗炎药（NSAIDs）在其结构中都含有一个羧酸。然而，目前尚不清楚这些药物是否抑制 CYP4A11 活性。本研究使用人肝微粒体（HLMs）和重组 CYP4A11 研究了酸性 NSAIDs 对 CYP4A11 活性的抑制作用。舒林酸硫醚、布洛芬和氟比洛芬可有效降低 HLMs 和重组 CYP4A11 的荧光素-4A O-脱甲基酶活性（在 100μM 抑制剂浓度下抑制率为 30-96%），而水杨酸、阿司匹林、双氯芬酸、甲芬那酸、吲哚美辛、依托度酸、酮洛芬、洛索洛芬、S-萘普生、普拉洛芬、扎托洛芬和奥沙普嗪的抑制活性较弱（抑制率最高达 23%）。在所测试的药物中，舒林酸硫醚是 CYP4A11 活性的最强抑制剂。舒林酸硫醚对 HLMs（K=3.38μM）和重组 CYP4A11（K=4.19μM）的抑制的动力学分析表明为混合型抑制。舒林酸硫醚是舒林酸（亚砜形式）的一种药理活性代谢物，也被氧化为舒林酸亚砜。为了阐明舒林酸硫醚中硫原子在抑制 CYP4A11 中的作用，研究了舒林酸硫醚及其氧化形式对 CYP4A11 活性的抑制作用。对 HLMs 的抑制强度顺序为舒林酸硫醚>舒林酸>舒林酸亚砜；IC 值分别为 6.16、52.7 和 71.6μM。本研究结果表明，舒林酸硫醚是 CYP4A11 的一种强效抑制剂。这些结果以及 CYP4A11 与舒林酸硫醚及其氧化形式的分子建模表明，舒林酸硫醚的硫原子及其羧酸在抑制 CYP4A11 中发挥重要作用。
