Involvement of heme in the transcriptional activation of CYPIIB1/B2 gene by phenobarbitone in rat liver--studies with succinylacetone.
Earlier studies in this laboratory had implicated heme to function as a positive modulator of phenobarbitone-mediated activation of CYPIIB1/B2 gene transcription in rat liver. However, recent reports have indicated that succinylacetone, a specific inhibitor of delta-aminolevulinate dehydrase, does not affect this process. The present studies indicate that succinylacetone does inhibit the phenobarbitone-mediated increase in CYPIIB1/B2 mRNAs and their transcription in rat liver at early time points (45 min to 3 h), but the inhibition is not pronounced at later time points (16 h). Succinylacetone is a weaker inhibitor of heme biosynthesis than CoCl2, 3-amino-1,2,4-triazole, or thioacetamide used earlier in this laboratory. Succinylacetone induces delta-aminolevulinate synthase, whereas the other compounds depress the levels of the enzyme. There is a good correlation between the amount of freshly synthesized nuclear heme pool and the activation of CYPIIB1/B2 transcription by phenobarbitone. A model implicating a nuclear heme pool regulating the transcription of delta-aminolevulinate synthase, CYPIIB1/B2, and heme oxygenase genes is proposed.
Venkateswar
V
V
Department of Biochemistry, Indian Institute of Science, Bangalore.
Padmanaban
G
G
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006418:Heme / Q000235:genetics* / Q000378:metabolism; D006537:Heptanoates / Q000494:pharmacology; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008297:Male; D010634:Phenobarbital / Q000494:pharmacology; D000623:Porphobilinogen Synthase / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects
D006537:Heptanoates; D012333:RNA, Messenger; D006418:Heme; C020804:succinylacetone; D003577:Cytochrome P-450 Enzyme System; D000623:Porphobilinogen Synthase; D010634:Phenobarbital