The major polycyclic hydrocarbon (PAH)-inducible rat cytochrome P450, i.e., P45OIA1 appears regulated by cis and trans factors. We have previously proposed that a 4S PAH-binding protein interacts with a specific cis element, the PRE, in activating the transcription of the P45OIA1 gene. In addition, others have demonstrated the existence of a negative response element which suppresses the expression of this gene. During the tenure of this research grant, we will a) determine the nature of the cis regulatory elements in this gene, including the sequence to which PAH's such as 3- methylcholanthrene and benzo(a)pyrene interact, the PAH regulatory element (PRE), b) study the regulation of the P45OIAl gene by the 4S PAH-binding protein and define its action in some detail as a trans-activator, c) study the role of methylation and of nuclease sensitive sites in the regulation of this gene during liver ontogeny, d) define the action of the negative regulatory element (NRE), of a protein that interacts with the NRE and the interaction-between the PRE and NRE (and of their proteins) in governing expression of the P45OIAl gene, e) study the reason for the non-effectiveness of the glucocorticoid response elements (GRE) in regulating the expression of this gene in the absence of PAH'S, and f) determine the effects of androgens upon P45OIAI expression in an attempt to explain the sex difference in rat liver. These studies form part of our long-term goal to understand the regulation of the P45OIAl gene as it participates in mutagenesis, teratogenesis and carcinogenesis.
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