贡献人类细胞色素p - 450的亚型的新陈代谢最简单的吩噻嗪安定丙嗪。

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Wojcikowski J, Pichard-Garcia L, Maurel P,丹尼尔佤邦

贡献人类细胞色素p - 450的亚型的新陈代谢最简单的吩噻嗪安定丙嗪。

Br J杂志。2003年4月,138 (8):1465 - 74。doi: 10.1038 / sj.bjp.0705195。

PubMed ID

12721102 (在PubMed

]

文摘

1。本研究的目的是识别人类细胞色素p - 450亚型(cyp)参与5-sulphoxidation和最简单的去甲基吩噻嗪安定丙嗪在人类肝脏。2。体外实验进行了以下模型:(A)。研究丙嗪在肝微粒体代谢——(A)。丙嗪的代谢率之间的相关性和cyp的水平和活动;(b)。的影响特定抑制剂丙嗪的代谢率(抑制剂:CYP1A2-furafylline CYP2D6-quinidine,体内CYP2A6基因表现+ CYP2E1-diethyldithiocarbamic酸,CYP2C9-sulfaphenazole, CYP2C19-ticlopidine, CYP3A4-ketoconazole);(B)。丙嗪由人类cyp cDNA-expressed生物转化(Supersomes 1 a1, a2, 2 a6, 2 b6, 2 c9, 2 c19 2 e1, 3 a4);(C),丙嗪新陈代谢的主要文化人类肝细胞治疗与特定的诱导物(rifampicin-CYP3A4 CYP2B6 CYP2C诱导物,2、3、7日8-tetrachlordibenzeno-p-dioxin (TCDD) -CYP1A1/1A2诱导物)。3所示。在人类肝微粒体,形成丙嗪5-sulphoxide和N-desmethylpromazine明显与CYP1A2和ethoxyresorufin O-deethylase和乙酰苯胺4-hydroxylase活动,以及CYP3A4和环孢菌素氧化酶的活动。 Moreover, the formation of N-desmethylpromazine was correlated well with S-mephenytoin 4'-hydroxylation. 4. Furafylline (a CYP1A2 inhibitor) and ketoconazole (a CYP3A4 inhibitor) significantly decreased the rate of promazine 5-sulphoxidation, while furafylline and ticlopidine (a CYP2C19 inhibitor) significantly decreased the rate of promazine N-demethylation in human liver microsomes. 5. The cDNA-expressed human CYPs generated different amounts of promazine metabolites, but the rates of CYP isoforms to catalyse promazine metabolism at therapeutic concentration (10 microM) was as follows: 1A1>2B6>1A2>2C9>3A4>2E1>2A6>2D6>2C19 for 5-sulphoxidation and 2C19>2B6>1A1>1A2>2D6>3A4>2C9>2E1>2A6 for N-demethylation. The highest intrinsic clearance (V(max)/K(m)) was found for CYP1A subfamily, CYP3A4 and CYP2B6 in the case of 5- sulphoxidation, and for CYP2C19, CYP1A subfamily and CYP2B6 in the case of N-demethylation. 6. In a primary culture of human hepatocytes, TCDD (a CYP1A subfamily inducer), as well as rifampicin (mainly a CYP3A4 inducer) induced the formation of promazine 5-sulphoxide and N-desmethylpromazine. 7. Regarding the relative expression of various CYPs in human liver, the obtained results indicate that CYP1A2 and CYP3A4 are the main isoforms responsible for 5-sulphoxidation, while CYP1A2 and CYP2C19 are the basic isoforms that catalyse N-demethylation of promazine in human liver. Of the other isoforms studied, CYP2C9 and CYP3A4 contribute to a lesser degree to promazine 5-sulphoxidation and N-demethylation, respectively. The role of CYP2A6, CYP2B6, CYP2D6 and CYP2E1 in the investigated metabolic pathways of promazine seems negligible.

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药物酶

药物	酶	类	生物	药理作用	行动
丙嗪	细胞色素P450 1 a2	蛋白质	人类	未知的	底物 抑制剂	细节
丙嗪	细胞色素P450 2 c19	蛋白质	人类	未知的	底物	细节
丙嗪	细胞色素P450 2 c9	蛋白质	人类	未知的	底物	细节
丙嗪	细胞色素P450 2 d6	蛋白质	人类	未知的	底物	细节
丙嗪	细胞色素P450 3 a4	蛋白质	人类	未知的	底物	细节