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-tp ans (AT) or 9-cis-retinoic (9cRA) showed a 2.5-fold increase in reporter activity. The P4503F2 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 muM 9cRA stimulated promoter activity 10-fold at 12 h while 20 muM ATRA increased activity 2.5-fold after 48 h. Cotransfection with RXR alpha can enhance reporter activity 2.5-fold, while RXR alpha /RAR alpha increased activity 1.5-fold. In contrast, cotransfection with RAR alpha 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 TGA-CCT) at -708 able to bind RXR alpha /RAR alpha heterodimers and mediate the repressive response of ATRA. These results indicate that retinoic acid can regulate CYP4F2 gene activity with RXR alpha heterodimers stimulating while RAR alpha functioning to repress CYP4F2 gene expression.