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Mechanisms for constitutive and developmental regulation of rat hepatic cytochrome P450 genes

Most constitutively-expressed rat hepatic P450 genes become transcriptionally activated after birth. The CYP2E1 and CYP2C6 genes begin to be expressed at two distinct developmental stages in both male and female rats; within a few hours after birth and just prior to puberty between 3 and 4 weeks of age, respectively. To determine the mechanisms by which these genes are regulated, we used transfection of heterologous gene-P450 promoter constructs in conjunction with upstream DNA deletion analysis and in vitro DNA binding assays, to delineate the c/'s-acting elements associated with transcriptional activity. To determine the frans-acting factors responsible for expression of the CYP2E1 and CYP2C6 genes, co-transfection studies were carried out using various cDNA-expressed, hepatocyte-enriched transcription factors and direct DNA binding assays using recombinant factors produced in bacteria. The hepatocyte-enriched factor HNF-1a is able to activate the CYP2E1 gene in both in vitro transcription and in co-transfection fra/is-activation assays. This factor is produced in rats just after birth where it is able to bind to a c/'s-acting element upstream of CYP2E1. It is unclear whether expression of HNF-1a is sufficient to activate CYP2E1 or whether changes in chromatin structure permit its binding. Other studies established that the factor DBP, responsible for maintenance of serum albumin expression in adult rats, binds to DNA upstream of the CYP2C6 gene and transactivates the CYP2C6 promoter in DBP-minus hepatoma cells. Interestingly, the factor C/EBP, which can frans-activate the serum albumin promoter through binding to the albumin DBP-binding element, is unable to trans-activate the CYP2C6 gene. This factor can, however, bind the CYP2C6 DBP-binding region. Expression of DBP during rat development is coincident with expression of CYP2C6 further suggesting that activation of CYP2C6 transcription at around puberty is due, in part, to developmentallyprogrammed expression of DBP.