DIFFERENTIAL REGULATION OF THE CYTOCHROME-P450 3A1 GENE-TRANSCRIPTIONBY DEXAMETHASONE IN IMMATURE AND ADULT-RAT LIVER

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. B iochem. Biophys. 298, 714-725]. In the present study we investigate th e relative importance of cytochrome P450 3A1 gene transcription on the adaptive response to the synthetic glucocorticoid dexamethasone, by m easuring the time-course run-on transcription rate and concomitant mRN A accumulation in the male rat liver at two different ontological deve lopmental stages. The primary (direct) or secondary (dependent on prot ein neo-synthesis) nature of the in vivo inductive response to dexamet hasone and to pregnenolone 16 alpha-carbonitrile, is further investiga ted by inhibiting translation by cycloheximide pretreatment. The induc tion of cytochrome P450 3A1 gene transcription by the anti-glucocortic oid pregnenolone 16 alpha-carbonitrile is demonstrated to occur throug h a secondary mechanism, requiring ongoing protein biosynthesis, regar dless of the developmental stage of the animals. Conversely, a signifi cant developmentally controlled change is observed in the inductive re sponse of the cytochrome P450 3A1 gene to dexamethasone, characterized by a markedly delayed transcriptional activation in the adult rat liv er (90 day old) as compared to the immature rat liver (21 day old). Th is is consistent with the net primary response of the cytochrome P450 3A1 gene to dexamethasone demonstrated in this study to occur in the i mmature rat liver and almost lost at the adult stage, when protein neo -synthesis becomes essential for the inductive response. Our results d emonstrate (a) a difference in the mechanisms underlying induction of the cytochrome P450 3A1 gene by the glucocorticoid agonist dexamethaso ne and by the antagonist pregnenolone 16 alpha-carbonitrile, and (b) a n important change in the mechanisms of the inductive response to dexa methasone, associated with the immature/adult liver phenotype transiti on. This indicates the participation of specific labile transcription factors in the induction of cytochrome P450 3A1 gene by the synthetic glucocorticoids.