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Human liver leukotriene B4 (LTB4) omega-hydroxylase (CYP4F2) plays an important role in the metabolic inactivation and degradation of LTB4, a potent mediator of inflammation. The regulatory mechanism for the transcription of CYP4F2 has not yet been clarified. Here, we report that CYP4F2 is constitutively expressed in a human hepatoma cell line, HepG2, and is not induced by clofibrate. We isolated the gene encoding CYP4F2 and determined its genomic organization and the functional activity of its promoters. The CYP4F2 gene contains at least 13 exons with its open reading frame being encoded from exon II to exon XIII. Exon I includes 49 bp of a 5' untranslated sequence. The structure of this gene is very similar to that of the CYP4F3 gene earlier reported by Kikuta et al. (DNA Cell Biol 1998;17:221-230). The 5' flanking sequence downstream from -165 of the CYP4F2 gene has 75% similarity to the corresponding region of the CYP4F3 gene. However, common putative regulating elements in the two human CYP4F genes were not detected except for the TATA box. The elements recognized by nuclear receptors were not observed within its 5' flanking region. Deletion of the 5' flanking regions containing putative regulating elements recognized by HNF-3beta, CDP CR, and p300 caused alterations in the transcriptional activity. The region from -83 to -67 was necessary for transcription, but the TATA sequence was not. Our results indicate that the human two CYP4F genes evolved by duplication and alterations of the transcription regulation region and the site of exon III.