The cytochrome P450 gene superfamily comprises at least eight gene families: (i) 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; in the lay press called """"""""dioxin"""""""")-inducible; (ii) phenobarbital-inducible; (iii) steroid-inducible; (iv) clofibrate-inducible; and gene(s) involved in (v) steroid 11Beta-hydroxylation; (vi) cholesterol side-chain cleavage; (vii) steroid 17Alpha-hydroxylation; and (viii) steroid C21-hydroxylation. This laboratory has studied most intensively the TCDD-inducible P450 gene family, which has two members, P-1-450 and P-3-450. In mouse P-1-450 and P-3-450 are but two genes in the [Ah] complex, a """"""""battery"""""""" of at least five genes activated by polycyclic aromatic inducers such as TCDD and regulated by the aromatic hydrocarbon (Ah) receptor. Many of these proteins are being purified, antibodies developed and cDNA and genomic clones isolated and sequenced in order to understand regulatory expression of this gene battery believed to play an important role early in development. There are interesting differential transcriptional regulatory mechanisms for activation of the P-1-450 and P-3-450 genes, as well as striking developmental and tissue-specific differences in gene expression. Upstream P-1-450 regulatory sequences include a promoter region, a negative control element (involved in a negative autoregulatory loop), and a TCDD-responsive enhance element (about 1,000 bases upstream from the mRNA cap site) that spans more than 200 bp and includes one or more enhancers of constitutive gene expression as well. Restriction fragment length polymorphisms have been found with both the human P-1-450 and P-3-450 genes on chromosome 15. One long-range goal of this laboratory is to develop assays, based on recombinant DNA technology, to assess the human Ah phenotype and other pharmacogenetic disorders. Such assays may predict who is at increased risk for certain types of environmentally-caused birth defects, cancers, and toxicity.
