Acetaminophen analog N-acetyl-m-aminophenol, but not its reactive metabolite, N-acetyl-p-benzoquinone imine induces CYP3A activity via inhibition of protein degradation
Acetaminophen analog N-acetyl-m-aminophenol, but not its reactive metabolite, N-acetyl-p-benzoquinone imine induces CYP3A activity via inhibition of protein degradation
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对乙酰氨基酚类似物 N-乙酰基-间氨基苯酚，但不是其反应性代谢物 N-乙酰基-对苯醌亚胺，通过抑制蛋白质降解诱导 CYP3A 活性
DOI：
10.1016/j.bbrc.2017.03.073
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Ohta S.
中科院分区：
文献类型：
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作者：
Santoh M;Sanoh S;Ohtsuki Y;Ejiri Y;Kotake Y;Ohta S.
已知细胞色素P450（CYP 3A）3A亚家族成员代谢各种类型的药物，这突出了了解依赖于CYP 3A诱导或抑制的药物-药物相互作用（DDI）的重要性。虽然CYP 3A成员的转录调控被广泛理解，但翻译后调控需要阐明。对乙酰氨基酚（acetaminophen，APAP）通过抑制蛋白质降解而诱导CYP 3A活性，并提出了DDI的新概念，APAP的反应性代谢产物N-乙酰对苯醌亚胺（NAPQI）可引起细胞内还原型谷胱甘肽（GSH）耗竭。我们的目的是检查是否NAPQI而不是APAP本身可以引起对蛋白质降解的抑制作用。我们发现，N-乙酰-L-半胱氨酸，GSH的前体，和1-氨基苯并三唑，一种非选择性的CYP 3A 1/23抑制剂，对APAP影响的CYP 3A 1/23蛋白水平没有影响。因此，我们使用APAP类似物来测试CYP 3A 1/23 mRNA水平、蛋白水平和CYP 3A活性。发现APAP的位置异构体N-乙酰间氨基苯酚（AMAP）对CYP 3A 1/23蛋白降解有相同的抑制作用，而羧基取代的对乙酰氨基苯甲酸（PAcBA）对CYP 3A 1/23蛋白降解无抑制作用。AMAP和PAcBA不能被氧化成醌亚胺形式，如NAPQI，因此抑制作用可能取决于APAP的特定化学结构。
Cytochrome P450 (CYP) 3A subfamily members are known to metabolize various types of drugs, highlighting the importance of understanding drug–drug interactions (DDI) depending on CYP3A induction or inhibition. While transcriptional regulation of CYP3A members is widely understood, post-translational regulation needs to be elucidated. We previously reported that acetaminophen (APAP) induces CYP3A activity via inhibition of protein degradation and proposed a novel DDI concept.N-Acetyl-p-benzoquinone imine (NAPQI), the reactive metabolite of APAP formed by CYP, is known to cause adverse events related to depletion of intracellular reduced glutathione (GSH). We aimed to inspect whether NAPQI rather than APAP itself could cause the inhibitory effects on protein degradation. We found thatN-acetyl-l-cysteine, the precursor of GSH, and 1-aminobenzotriazole, a nonselective CYP inhibitor, had no effect on CYP3A1/23 protein levels affected by APAP. Thus, we used APAP analogs to test CYP3A1/23 mRNA levels, protein levels, and CYP3A activity. We foundN-acetyl-m-aminophenol (AMAP), a regioisomer of APAP, has the same inhibitory effects of CYP3A1/23 protein degradation, whilep-acetamidobenzoic acid (PAcBA), a carboxy-substituted form of APAP, shows no inhibitory effects. AMAP and PAcBA cannot be oxidized to quinone imine forms such as NAPQI, so the inhibitory effects could depend on the specific chemical structure of APAP.