Comparison of the flanking regions and introns of the mouse 2,3,7,8-tetrachlorodibenzo-p-dioxin-inducible cytochrome P1-450 and P3-450 genes.

The C57BL/6N inbred mouse cytochrome P1-450 and P3-450 genes, two genes in the same family and under control by the Ah receptor, have been completely sequenced. The transcription initiation sites were confirmed by primer extension studies. An additional 823 and 893 bp of the 5' upstream flanking regions of P1-450 and P3-450, respectively, and 1771 and 1251 bp of the 3' downstream flanking regions of P1-450 and P3-450, respectively, were sequenced and studied. P1-450 exons total 2619 nucleotides, and the gene spans 6215 bp. P3-450 exons total 1892 nucleotides, and the gene spans 6716 bp. Three interesting highly homologous regions of 11 or 12 bp, upstream between -280 and -530 from the cap site of both genes, are noted as possible candidates for binding by the inducer-Ah receptor complex (and/or other DNA-binding regulatory proteins). Several stretches of DNA upstream from the cap site, in several introns, and in the 3' flanking region of both genes have a high degree of homology with known core enhancer sequences. Other interesting stretches (DNA with Z-DNA-forming properties, DNA with recombinational potential, highly repetitive and middle repetitive sequences between 50 and 360 bp in length, and "simple" sequences presumably having no function in gene expression) exist throughout many of the introns and flanking regions in both the positive and negative strands of both genes. The mouse 2,3,7,8-tetrachlorodibenzo-p-dioxin-inducible and rat phenobarbital-inducible P-450 genes were compared for the amino acid residue number at each exon-intron junction, the location in the coding triplet at which the exons are split, and homologies among introns and exons. It can be shown that these two gene families probably diverged from a common ancestor more than 200 million years ago and that P1-450 and P3-450 split from each other about 65 million years ago.