Regulation of CYP4F2 Leukotriene B4 ω-Hydroxylase by Retinoic Acids in HepG2 Cells

• Published in: Biochemical and biophysical research communications 2000-12, Vol.279 (3), p.864-871
• Main Authors: Zhang, Xiaolan, Hardwick, James P.
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; CYP4F2 gene transcription; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; Cytochrome P450 Family 4; Gene Expression Regulation, Enzymologic - drug effects; Humans; Hydroxylation; inflammation; Leukotriene B4 - metabolism; LTB4 and arachidonic P450 ω-hydroxylation; Molecular Sequence Data; RARE elements; retinoic acid; Tretinoin - pharmacology; Tumor Cells, Cultured; Up-Regulation
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1006/bbrc.2000.4020

The human CYP4F2 gene encodes a LTB4 ω-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 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.