Superinduction by Cycloheximide of Cytochrome P4502H1 and 5-Aminolevulinate Synthase Gene Transcription in Chick Embryo Liver

The present study examines the effect of inhibiting protein synthesis with cycloheximide on the induction of the genes for cytochrome P4502H1 (CYP2H1) and 5-aminolevulinate synthase (ALAS) in phenobarbitaltreated chick embryo livers. Phenobarbital administration caused a 10- to 15-fold increase in the levels of mRNAs for both CYP2HL and ALAS. Cycloheximide treatment alone also induced the levels of mRNA for CYP2H1 and ALAS by 7- and 3-fold, respectively, but in combination, cycloheximide and phenobarbital elicited an additional effect resulting in a 33- and 40-fold increase, respectively. To investigate whether these effects were due to transcriptional activation or a post-transcriptional mechanism, nuclear transcription run-on experiments were conducted. The observed changes in mRNA levels for CYP2H1 and ALAS were shown to be predominantly due to changes in the rate of transcription of the respective genes. These findings establish that drug induction of the CYP2H1 and ALAS genes can proceed in the almost complete absence of protein synthesis and also imply that a labile repressor protein may be involved in modulating expression of these genes. In addition, these results indicate that drug induction of ALAS does not require concomitant synthesis of P450 apoprotein.