Induction of the CYP2B genes by triphenyldioxane treatment in the rat liver

Triphenyldioxane (TPD) is a potent phenobarbital-type (PB) inducer of the CYP2B cytochrome isoforms, the inducing effect of which is one order of magnitude higher than PB. The fact that TPD is unable to induce CYP2B genes having the proximal promoter disrupted (mouse Cyp2b10) suggests an existence of the proximal promoter-dependent mechanism of the CYP2B induction. So a TPD-dependent activation of the nuclear proteins to the binding with Barbie-box sequence (the most conservative part of the proximal promoter) was studied. In the nuclear extracts from the intact rat liver there were detected five proteins that could be activated to the Barbie-box binding by the TPD treatment in vitro (II, III, NI, NII and NIII). The first three were effected also by another PB-like inducers tested (PB and TCPOBOP), when NII and NIII complexes were formed under the influence of TPD only. It is possible that a direct activation of the NII and NIII proteins by TPD exists as (3)H-labeled TPD was detected in the composition of NII and NIII complexes. However, both of them disappeared from the nuclear extracts after the long exposure time with TPD (6 h or more). A short induction by the direct intra-liver delivery of TPD (15-30 min) led to the stabile activation of one TPD-specific protein. Apart from the activation of the Barbie-box-binding protein, the short TPD treatment caused the activation of three nuclear proteins being able to interact with the NR1 sequence of the distal promoter PBREM element. These findings suggest that TPD is really the first member of the PB-like inducers family for which a special mechanism of CYP2B induction may exist.