Human cytochrome P450s involved in the metabolism of 9-cis- and 13-cis-retinoic acids
Human cytochrome P450s involved in the metabolism of 9-cis- and 13-cis-retinoic acids
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DOI：
10.1016/s0006-2952(01)00925-x
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发表时间：
2002-03-01
影响因子：
5.8
通讯作者：
Chabot, GG
中科院分区：
文献类型：
--
作者：
Marill, J;Capron, CC;Chabot, GG
这项工作的目的是通过使用包括人肝微粒体（活性和抑制的相关性）和表达单个CYP的淋巴母细胞微粒体在内的组合技术，鉴定参与维甲酸（RA）异构体9-顺式和13-顺式RA代谢的主要人类细胞色素p450 （CYPs）。关于9-顺式ra。4-OH-和4-氧-9-顺- ra在人肝微粒体中形成，它们的形成与CYPs 3A4/5、2136、2C8、2A6和2C9相关。使用表达单个人CYP的淋巴母细胞微粒体鉴定CYPs 2C9 > 2C8 > 3A7在4- oh -9-顺式ra的形成中最活跃。在13-顺式ra中，与CYPs 2136、2C8、3A4/5和2A6相关的P450特异性活性与4-OH-和4-氧-13-顺式ra的形成相关。表达单个CYP的微体在4- oh -13-顺式ra的形成过程中鉴定出CYP 3A7、2C8、4A11、1B1、2136、2C9、2C19、3A4（活性降低）。在人肝微粒体中使用cypp特异性抑制剂表明，磺胺苯唑（72%）和槲皮素（66%）对4- oh -9-顺式ra的形成有最好的抑制作用，而酮康唑和罗林霉素对其形成的抑制作用分别为55%和38%；troleandomycin（54%）和酮康唑（46%）对4- oh -13-顺式ra的形成有较好的抑制作用，槲皮素的抑制作用较弱（14%）。综上所述，成人CYPs 2C9、2C8、3A4在9-顺式ra代谢中具有活性，而CYPs 3A4和2C8在13-顺式ra代谢中具有活性。胎儿型CYP3A7也被鉴定为在9-顺式或13-顺式ra代谢中非常活跃。这些人类CYPs在RA异构体的生物反应或耐药性中的作用仍有待确定。(C) 2002爱思唯尔科学有限公司版权所有。
The purpose of this work was to identify the principal human cytochrome P450s (CYPs) involved in the metabolism of the retinoic acid (RA) isomers, 9-cis- and 13-cis-RA, by using a combination of techniques including human liver microsomes (correlation of activity and inhibition), and lymphoblast microsomes expressing a single CYP. Concerning the 9-cis-RA. 4-OH- and 4-oxo-9-cis-RA were formed with human liver microsomes, and their formation correlated with activities linked to CYPs 3A4/5, 2136, 2C8, 2A6, and 2C9. The use of lymphoblast microsomes expressing a single human CYP identified CYPs 2C9 > 2C8 > 3A7 as the most active in the formation of 4-OH-9-cis-RA. With regard to 13-cis-RA, specific P450 activities linked to CYPs 2136, 2C8, 3A4/5, and 2A6 were correlated with the formation of 4-OH- and 4-oxo-13-cis-RA. Microsomes expressing a single CYP identified CYPs 3A7, 2C8, 4A11, 1B1, 2136, 2C9, 2C19, 3A4 (decreasing activity) in the formation of 4-OH-13-cis-RA. The use of CYP-specific inhibitors in human liver microsomes disclosed that the formation of the 4-OH-9-cis-RA was best inhibited by sulfaphenazole (72%) and quercetin (66%), whereas ketoconazole and troleandomycin inhibited its formation by 55 and 38%, respectively; the formation of 4-OH-13-cis-RA was best inhibited by troleandomycin (54%) and ketoconazole (46%), whereas quercetin was a weak inhibitor (14%). In conclusion, adult human CYPs 2C9, 2C8, 3A4 have been identified as active in the 9-cis-RA metabolism, whereas CYPs 3A4 and 2C8 were active in 13-cis-RA metabolism. The fetal form CYP3A7 was also identified as very active in either 9-cis- or 13-cis-RA metabolism. The role of these human CYPs in the biological response or resistance to RA isomers remains to be determined. (C) 2002 Elsevier Science Inc. All rights reserved.