Regulation of CYP4F2 leukotriene B4 omega-hydroxylase by retinoic acids in HepG2 cells.
Regulation of CYP4F2 leukotriene B4 omega-hydroxylase by retinoic acids in HepG2 cells.
复制标题
HepG2 细胞中视黄酸对 CYP4F2 白三烯 B4 omega-羟化酶的调节。
DOI：
10.1006/bbrc.2000.4020
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发表时间：
2000
影响因子：
3.1
通讯作者：
Hardwick,JP
中科院分区：
文献类型：
--
作者：
Zhang,X;Hardwick,JP
人CYP 4F 2基因编码LTB 4 ω-羟化酶P450，在肝脏和肾脏中显著表达，其功能是代谢和抑制促炎性类花生酸、LTB 4和花生四烯酸。用CYP 4F 2 −506/-6或−1727/-6启动子报告基因构建体转染并用全反式（AT）或9-顺式维甲酸（9 cRA）处理的HepG 2细胞显示报告基因活性增加2.5倍。9 cRA处理后HepG 2细胞中P4504 F2蛋白含量增加2.5倍，而ATRA处理后则无此作用。剂量反应和时间过程研究表明，10 μM 9 cRA在12 h时激活启动子活性10倍，而20 μM ATRA在48 h后激活活性2.5倍。与RXRα共转染可使报告基因活性提高2.5倍，而RXRα/RARα共转染可使报告基因活性提高1.5倍。与此相反，RARα共转染降低了视黄酸30%的报告活性。CYP 4F 2基因中的三个区域对维甲酸有反应，其中DR 1 RARE元件（CCTCCT G TGACCT）位于−708，能够结合RXRα/RARα异二聚体并介导ATRA的抑制反应。这些结果表明，视黄酸可通过RXRα异二聚体促进CYP 4F 2基因表达而RARα抑制CYP 4F 2基因表达来调节CYP 4F 2基因的活性。
The human CYP4F2 gene encodes a LTB4ω-hydroxylase P450 prominently expressed in liver and kidney that functions to metabolize and inactivate the pro-inflammatory eicosanoids, LTB4and arachidonic acid. HepG2 cells transfected with CYP4F2 −506/-6 or −1727/-6 promoter reporter constructs and treated with either all-trans (AT) or 9-cis-retinoic (9cRA) showed a 2.5-fold increase in reporter activity. The P4504F2 protein content in HepG2 cells treated with 9cRA increased 2.5-fold, but not with ATRA. Dose response and time course studies revealed that 10 μM 9cRA stimulated promoter activity 10-fold at 12 h while 20 μM ATRA increased activity 2.5-fold after 48 h. Cotransfection with RXRα can enhance reporter activity 2.5-fold, while RXRα/RARα increased activity 1.5-fold. In contrast, cotransfection with RARα decreased reporter activity by retinoic acid 30%. Three regions in the CYP4F2 gene are responsive to retinoic acid with the DR1 RARE element (CCTCCT G TGACCT) at −708 able to bind RXRα/RARα heterodimers and mediate the repressive response of ATRA. These results indicate that retinoic acid can regulate CYP4F2 gene activity with RXRα heterodimers stimulating while RARα functioning to repress CYP4F2 gene expression.