Abstract
Cytochrome P450s including in the CYP3A subfamily are involved in metabolism of clinically relevant substrates as well as numerous endogenous compounds. CYP3A forms are induced by the pretreatment with many drugs, but show the different induction profile between experimental animals and human. We have been studied the activation mechanism of rat CYP3A1/2 gene expression. Level of the transcriptional activation, however, varied among cultured-cell lines. These results prompted us to study in vivo induction mechanism of human CYP3A4 gene expression by use of adenovirous expression vector (AdCYP3A4-362), which was constructed with a proximal promoter region (-362 to +11) of the CYP3A4 gene and a reporter gene. Induction level of CYP3A4 gene expression differed not only among drugs but also among cultured-cell lines. In Hep G2 cells, dexamethasone and clotrimazole induced the gene expression, but rifampicin did not. In contrast, rifampicin induced the gene expression in LS174T cells. Therefore AdCYP3A4-364 was injected into ddy mouse and measured the reporter activity and also mouse liver CYP3A activity. Induction profile of CYP3A4 gene expression in mouse liver agreed well with that of mouse CYP3A activity. A mutation study of a receptor binding region (ER-6) showed the diminished induction level of CYP3A4 gene expression, but not of mouse CYP3A activity. These results strongly suggest that in vivo study of the gene transcriptional activation is very important to assess the induction profile of CYP3A4 gene expression by drugs.
