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-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.
Dwarki
V J
VJ
Department of Biochemistry, Indian Institute of Science, Bangalore.
Francis
V N
VN
Bhat
G J
GJ
Padmanaban
G
G
D000502:Allylisopropylacetamide / Q000494:pharmacology; D000640:Amitrole / Q000494:pharmacology; D000818:Animals; D001059:Apoproteins / Q000378:metabolism*; D003035:Cobalt / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005786:Gene Expression Regulation; D006418:Heme / Q000502:physiology*; D006427:Hemin / Q000494:pharmacology; D008297:Male; D010634:Phenobarbital / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats
D001059:Apoproteins; D012333:RNA, Messenger; D000502:Allylisopropylacetamide; D003035:Cobalt; D006418:Heme; D006427:Hemin; D003577:Cytochrome P-450 Enzyme System; C018021:cobaltous chloride; D010634:Phenobarbital; D000640:Amitrole