Dwarki V J, Francis V N, Bhat G J, Padmanaban G
Department of Biochemistry, Indian Institute of Science, Bangalore.
J Biol Chem. 1987 Dec 15;262(35):16958-62.
2-Allylisopropylacetamide, a porphyrinogen which decreases the microsomal and cytosolic heme pools, is a phenobarbitone-like inducer of cytochrome P-450(b + e) messenger RNAs in rat liver. The porphyrinogen, however, does not affect the nuclear heme pool and enhances the transcription of cytochrome P-450(b + e) messenger RNAs strikingly. Inhibitors of heme biosynthesis, such as CoCl2 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) messenger RNAs. Administration of exogenous heme at a very low concentration (25 micrograms/100 g) is able to counteract the inhibitory effects of the heme biosynthetic inhibitors. Addition of heme in vitro to heme-depleted nuclei leads to a significant increase in the transcription rates for cytochrome P-450(b + e) messenger RNAs. 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 messenger RNA levels. Under conditions of 2-allylisopropylacetamide treatment, the cytochrome P-450 messenger RNA is translated, but the newly synthesized apoprotein undergoes rapid degradation. It is concluded that heme is a positive modulator of cytochrome P-450 gene transcription and is also required to stabilize the freshly synthesized apoprotein.
2-烯丙基异丙基乙酰胺是一种能减少微粒体和胞质血红素池的卟啉原，它是大鼠肝脏中细胞色素P-450(b + e)信使RNA的苯巴比妥样诱导剂。然而，该卟啉原并不影响细胞核血红素池，却能显著增强细胞色素P-450(b + e)信使RNA的转录。血红素生物合成抑制剂，如氯化钴和3-氨基-1,2,4-三唑，可降低包括细胞核血红素池在内的总血红素水平，它们能阻断2-烯丙基异丙基乙酰胺或苯巴比妥介导的细胞色素P-450(b + e)信使RNA转录增加。以极低浓度（25微克/100克）给予外源性血红素能够抵消血红素生物合成抑制剂的抑制作用。在体外向血红素缺乏的细胞核中添加血红素会导致细胞色素P-450(b + e)信使RNA的转录速率显著增加。与苯巴比妥不同，2-烯丙基异丙基乙酰胺在给药后12小时未能增加细胞色素P-450b蛋白的水平，尽管信使RNA水平有显著增加。在2-烯丙基异丙基乙酰胺处理的条件下，细胞色素P-450信使RNA会被翻译，但新合成的脱辅基蛋白会迅速降解。结论是，血红素是细胞色素P-450基因转录的正向调节剂，也是稳定新合成的脱辅基蛋白所必需的。
