Differential Regulation of the Cytochrome P450 3A1 Gene Transcription by Dexamethasone in Immature and Adult Rat Liver

Abstract

We have previously shown that the in vivo induction of cytochrome P450 3A1 by dexamethasone occurs through a sharp and early transcriptional activation in the immature rat liver that is drastically impaired in adults [Telhada, M. B., Pereira, T. M. & Lechner, M. C. (1992) Arch. Biochem. Biophys. 298, 714-725]. In the present study we investigate the relative importance of cytochrome P450 3A1 gene transcription on the adaptive response to the synthetic glucocorticoid dexamethasone, by measuring the time-course run-on transcription rate and concomitant mRNA accumulation in the male rat liver at two different ontological developmental stages. The primary (direct) or secondary (dependent on protein neo-synthesis) nature of the in vivo inductive response to dexamethasone and to pregnenolone 16 alpha-carbonitrile, is further investigated by inhibiting translation by cycloheximide pretreatment. The induction of cytochrome P450 3A1 gene transcription by the anti-glucocorticoid pregnenolone 16 alpha-carbonitrile is demonstrated to occur through a secondary mechanism, requiring ongoing protein biosynthesis, regardless of the developmental stage of the animals. Conversely, a significant developmentally controlled change is observed in the inductive response of the cytochrome P450 3A1 gene to dexamethasone, characterized by a markedly delayed transcriptional activation in the adult rat liver (90 day old) as compared to the immature rat liver (21 day old). This is consistent with the net primary response of the cytochrome P450 3A1 gene to dexamethasone demonstrated in this study to occur in the immature rat liver and almost lost at the adult stage, when protein neo-synthesis becomes essential for the inductive response. Our results demonstrate (a) a difference in the mechanisms underlying induction of the cytochrome P450 3A1 gene by the glucocorticoid agonist dexamethasone and by the antagonist pregnenolone 16 alpha-carbonitrile, and (b) an important change in the mechanisms of the inductive response to dexamethasone, associated with the immature/adult liver phenotype transition. This indicates the participation of specific labile transcription factors in the induction of cytochrome P450 3A1 gene by the synthetic glucocorticoids.