Regulation of cytochrome P-450 messenger RNA and apoprotein levels by heme

Abstract

2-Allylisopropylacetamide, a porphyrinogen which decreases the microsomal and cytosolic heme pools, is a phenobarbitone-like inducer of cytochrome P 4504(b+e) mRNAs in rat liver. The porphyrinogen, however, does not affect the nuclear heme pool and enhances the transcription of cytochrome P 450(b+e) mRNAs strikingly. Inhibitors of heme biosynthesis, such as $CoCl_2$ and 3-amino-1,2,4-triazole, which decrease the total heme levels including that of the nuclear heme pool, block the 2-allylisopropylacetamide- or phenobarbitone-mediated increase in the transcription of cytochrome P 450(b+e) mRNAs. Administration of exogenous heme at a very low concn. (25 \mug/100 g) is able to counteract the inhibitory effects of the heme biosynthetic inhibitors. Addn. of heme in vitro to heme-depleted nuclei leads to a significant increase in the transcription rates for cytochrome P 450(b+e) mRNAs. 2-Allylisopropylacetamide, unlike phenobarbitone, fails to increase the levels of cytochrome P-450b protein at 12 h after the drug administration, although there is a striking increase in the mRNA levels. Under conditions of 2-allylisopropylacetamide treatment, the cytochrome P 450 mRNA is translated, but the newly synthesized apoprotein undergoes rapid degrdn. Thus, heme is a pos. modulator of cytochrome P 450 gene transcription and is also required to stabilize the freshly synthesized apoprotei