Metabolism of retinol and retinoic acid by human liver cytochrome P450IIC8.
Metabolism of retinol and retinoic acid by human liver cytochrome P450IIC8.
复制标题
人肝细胞色素 P450IIC8 代谢视黄醇和视黄酸。
DOI：
10.1016/0003-9861(89)90112-4
复制
发表时间：
1989
影响因子：
3.9
通讯作者：
Lieber,CS
中科院分区：
文献类型：
--
作者：
Leo,MA;Lasker,JM;Raucy,JL;Kim,CI;Black,M;Lieber,CS
从9名受试者身上获得的肝微粒体被发现将视黄醇代谢为极性代谢物，包括4-羟基视黄醇。在含人肝脏P450IIC8的重组单加氧酶体系中，视黄醇转化为4-羟基视黄醇等极性代谢产物，aKmof为0.071，aVmaxof为1.73 nmol/min/nmol P450。另外两个纯化的人P450IIC9和P450IIE1都没有显示出明显的视黄醇羟化酶活性。用针对人P450IIC8的单特异性抗体进行的免疫印迹显示，人肝微粒体中存在相当数量的这种酶。该抗体显著抑制肝微粒体和P450IIC8重组体系的视黄醇代谢。用P450IIC8重组的体系也将维甲酸转化为极性代谢物。因此，本研究首次表明，人肝细胞色素P450对两种生理底物的代谢与一组“组成型”啮齿动物P450有关，这些P450被认为参与内源性化合物的代谢。通过参与维生素A代谢，P450IIC8可能参与维持促进细胞完整性（并反对癌症发展）的维生素A浓度与引起细胞毒性的维生素A浓度之间的平衡。
Liver microsomes obtained from nine subjects were found to metabolize retinol to polar metabolites, including 4-hydroxyretinol. In a reconstituted monooxygenase system containing human liver P450IIC8, retinol was converted to 4-hydroxyretinol and other polar metabolites, with aKmof 0.071 mmand aVmaxof 1.73 nmol/min/nmol P450. Neither P450IIC9 nor P450IIE1, two other purified human P450s, displayed significant retinol hydroxylase activity. Immunoblots performed with a monospecific antibody directed against human P450IIC8 revealed that appreciable amounts of this enzyme were present in human liver microsomes. The same antibody significantly inhibited retinol metabolism in liver microsomes and in the system reconstituted with P450IIC8. The system reconstituted with P450IIC8 also converted retinoic acid to polar metabolites. Thus, this study shows, for the first time, metabolism of two physiologic substrates by a human liver cytochrome P450 related to a group of “constitutive” rodent P450s believed to participate in the metabolism of endogenous compounds. Through its involvement in vitamin A metabolism, P450IIC8 may participate in maintaining the balance between those vitamin A concentrations that promote cellular integrity (and oppose the development of cancer) and those concentrations that cause cellular toxicity.