Developmental regulation of cytochrome P-450 (b+e) and glutathione transferase (Ya+Yc) gene expression in rat liver

The expression of cytochrome P-450 (b+e) and glutathione transferase (Ya+Yc) genes has been studied as a function of development in rat liver. The levels of cytochrome P-450 (b+e) mRNAs and their transcription rates are too low for detection in the 19-day old fetal liver before or after phenobarbitone treatment. However, glutathione transferase (Ya+Yc) mRNAs can be detected in the fetal liver as well as their induction after phenobarbitone treatment can be demonstrated. These mRNAs contents as well as their inducibility with phenobarbitone are lower in maternal liver than that of adult nonpregnant female rat liver. Steroid hormone administration to immature rats blocks substantially the phenobarbitone mediated induction of the two mRNA families as well as their transcription. It is suggested that steroid hormones constitute one of the factors responsible for the repression of the cytochrome P-450 (b+e) and glutathione transferase (Ya+Yc) genes in fetal liver

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

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