Characterization of a rabbit gene encoding a clofibrate-inducible fatty acid omega-hydroxylase: CYP4A6.

CYP4A6 mRNAs are induced in the rabbit liver and kidney following treatment with the antihyperlipidemic drug clofibrate. As a first step toward the elucidation of the mechanism controlling the induction of this and other CYP4A genes by clofibrate and other peroxisome proliferators, we have cloned and characterized the CYP4A6 gene. Genomic DNA containing the first 12 exons encoding CYP4A6 was isolated as three recombinant lambda phage, two of which were overlapping. The sequence of more than 1000 bp of the 5' upstream region as well as of the first 12 exons has been determined. These 12 exons encode all but approximately 80 bp at the 3' terminus of CYP4A6. Intron/exon junctions within the coding region of the gene are conserved relative to the rat CYP4A1 and CYP4A2 genes. Primer extension analysis indicates that transcription is initiated 33 bp upstream of the start codon. The CYP4A6 promoter region, like that of the rat CYP4A1 and CYP4A2 genes, does not contain a consensus TATA box. However, a consensus Sp1 recognition element is apparent at -46 bp upstream of the transcription start site. In addition, a sequence related to one of two regulatory elements that control the induction of the rat acyl-CoA oxidase gene by ciprofibrate is present upstream of the CYP4A6 promoter.