系统失活的人类重组P450 2 c9的非甾体类抗炎药物舒洛芬。

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O ' donnell JP, Dalvie DK, Kalgutkar, Obach RS

系统失活的人类重组P450 2 c9的非甾体类抗炎药物舒洛芬。

药物金属底座Dispos。2003年11月,31 (11):1369 - 77。doi: 10.1124 / dmd.31.11.1369。

PubMed ID

14570769 (在PubMed

]

文摘

非甾体类抗炎剂(+或-)舒洛芬[alpha-methyl-4 - (2-thienylcarbonyl) benzeneacetic酸]被评估为P450 2 c9钝化剂。(+或-)舒洛芬灭活baculovirus-expressed P450 2 c9的diclofenac-4-hydroxylase活动时间和浓度的方式,这是符合系统失活。活动后的损失符合一级动力学,舒洛芬NADPH-dependent。失活的动力学参数kinact和KI 0.091最低为1和3.7 microM,分别和分区比例是101。尽管P450 2 c9衬底S-warfarin部分防止失活,活性氧食腐动物,如超氧化物歧化酶和过氧化氢酶并没有阻止失活。广泛的透析不再生酶活性,表明失活进行通过共价修改。灭活P450 2 c9失去< 10%的能力形成一个CO-reduced复杂,表明失活可能导致脱辅基蛋白的共价修饰。添加外源的亲核试剂,如谷胱甘肽和氨基脲部分防止失活。除了5-hydroxysuprofen舒洛芬的新陈代谢,形成suprofen-glutathione共轭也明显在微粒体混合物中含有谷胱甘肽。飞行时间质谱显示质子化了的单一同位素的质量为566.1304共轭,符合C24H28N3O9S2的元素组成。 The mass spectrum indicated that conjugation had occurred on the intact thiophene ring, presumably via a thioether linkage. Further evidence for the formation of an electrophilic intermediate in suprofen-P450 2C9 incubations was obtained via the characterization of a novel pyridazine adduct upon addition of semicarbazide to the microsomal mixtures. The pyridazine derivative had a protonated monoisotopic mass of 257.0895 that was consistent with an elemental composition of C14H13O3N2. The formation of the stable pyridazine adduct suggested the generation of an electrophilic gamma-thioketo-alpha, beta-unsaturated aldehyde, analogous to that observed during the cytochrome P450-mediated bioactivation of furan. This electrophilic alpha, beta-unsaturated aldehyde represents a possible reactive intermediate that bioalkylates P450 2C9.

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药物酶

药物	酶	类	生物	药理作用	行动
舒洛芬	细胞色素P450 2 c9	蛋白质	人类	未知的	底物 抑制剂	细节