Up-regulation of CYP2A5 expression by porphyrinogenic agents in mouse liver.
Coumarin 7-hydroxylase (COH) activity is catalyzed by the Cyp2a-5 gene product (CYP2A5 enzyme) in mice. Mouse hepatic CYP2A5 expression is often increased in conditions in which other P450 forms are repressed, e.g. after the administration of heavy metals and other toxic agents known to affect cellular heme balance. In this study, the effect of various porphyrinogenic chemicals on the expression CYP2A5 and the key enzymes in heme metabolism was studied. Administration of single doses of griseofulvin (1000 mg/kg), thioacetamide (10 mg/kg) and aminotriazole (1000 mg/kg) to DBA/2 and C57BL/6 mice produced up to 10-fold increases in hepatic COH catalytic activity. Dramatic, up to 130-fold increases in response to the inducers was observed in the amount of CYP2A5 steady-state mRNA. The mRNA contents of aminolevulinate synthase, ferrochelatase and heme oxygenase were also increased to a variable extent, possibly reflecting feed-back regulatory mechanisms. In D2 mice the CYP2A5 inducing effect of aminotriazole and thioacetamide, but not that of griseofulvin, pyrazole and phenobarbital, was abolished by exogenously administered heme arginate. In the B6 strain heme arginate treatment increased CYP2A5 expression but it did not affect the induction caused by porphyrinogenic agents. These results show that porphyrinogenic agents act as efficient inducers of CYP2A5, and suggest that regulation of the transcription of the Cyp2a-5 gene could in some instances involve heme-sensitive factors.
Salonpää
P
P
Department of Pharmacology and Toxicology, University of Oulu, Finland.
Krause
K
K
Pelkonen
O
O
Raunio
H
H
D000624:5-Aminolevulinate Synthetase / Q000378:metabolism; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D065637:Cytochrome P-450 CYP2A6; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D015342:DNA Probes; D004790:Enzyme Induction / Q000187:drug effects; D005294:Ferrochelatase / Q000378:metabolism; D006418:Heme / Q000378:metabolism / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011165:Porphyrinogens / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D012194:RNA-Directed DNA Polymerase; D015854:Up-Regulation / Q000187:drug effects*
D015342:DNA Probes; D011165:Porphyrinogens; D012333:RNA, Messenger; D006418:Heme; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585520:Cyp2a5 protein, mouse; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2; D006419:Heme Oxygenase (Decyclizing); D000624:5-Aminolevulinate Synthetase; D012194:RNA-Directed DNA Polymerase; D005294:Ferrochelatase