The """"""""cytochrome P450"""""""" gene superfamily comprises a minimum of five 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) gene(s) involved in cholesterol side-chain cleavage; and (v) genes involved in the steroid C21-hydroxylase polymorphism. This laboratory has studied most intensively the TCDD-inducible P450 gene family, which has two members (P1-450 and P3-450 in the C57BL/6N mouse; P450c and P450d in rat; form 6 and form 4 in rabbit, respectively). In mouse P1-450 and P3-450 are but two genes in the [Ah] complex, a """"""""battery"""""""" of at least a dozen genes activated by polycyclic aromatic inducers such as TCDD and presumably regulated by the Ah (TCDD) 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. The P1-450 and P3-450 genes reside adjacent to one another near the Mpi-1 locus on mouse chromosome 9; their orthologs reside on human chromosome 15 and hamster chromosome 4. There are interesting differential transcriptional regulatory mechanisms for activation of the P1-450 and P3-450 genes, as well as striking developmental and tissue-specific differences in gene expression. Upstream P1-450 regulatory sequences include a promoter region, a negative cotrol element (involved in a negative autoregulatory loop), a positive control region (associating with the inducer-receptor complex), and an upstream activating element (presumably an endogenous enhancer). 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 if environmental-caused birth defects, cancers, and toxicity.
