Regulation of CYP4F2 leukotriene B4 omega-hydroxylase by retinoic acids in HepG2 cells.
The human CYP4F2 gene encodes a LTB4 omega-hydroxylase P450 prominently expressed in liver and kidney that functions to metabolize and inactivate the pro-inflammatory eicosanoids, LTB4 and 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 microM 9cRA stimulated promoter activity 10-fold at 12 h while 20 microM ATRA increased activity 2.5-fold after 48 h. Cotransfection with RXRalpha can enhance reporter activity 2.5-fold, while RXRalpha/RARalpha increased activity 1.5-fold. In contrast, cotransfection with RARalpha 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 RXRalpha/RARalpha heterodimers and mediate the repressive response of ATRA. These results indicate that retinoic acid can regulate CYP4F2 gene activity with RXRalpha heterodimers stimulating while RARalpha functioning to repress CYP4F2 gene expression.
Zhang
X
X
Department of Biochemistry and Molecular Pathology, Northeastern Ohio Universities College of Medicine, Rootstown, Ohio 44272, USA.
Hardwick
J P
JP
D000077556:Alitretinoin; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D000072470:Cytochrome P450 Family 4; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D006900:Hydroxylation; D007975:Leukotriene B4 / Q000378:metabolism; D008969:Molecular Sequence Data; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D000970:Antineoplastic Agents; D007975:Leukotriene B4; D000077556:Alitretinoin; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D000072470:Cytochrome P450 Family 4; C117480:CYP4F2 protein, human