cAMP mediated upregulation of CYP2A5 in mouse hepatocytes.
CYP2A5 is induced by a large number of chemicals including some cAMP modifiers. In a primary hepatocyte model, stimulation of the cAMP signal transduction pathway by glucagon and isoproterenol, acting via specific G-protein coupled plasma membrane receptors, produced up to 17-fold increases in the marker activity of CYP2A5, coumarin 7-hydroxylase. In contrast, glucagon and isoproterenol caused no significant effects on two other major CYP forms, CYP2B10 and CYP1A1/2. Phenobarbital (PB) elicited a 3-fold increase in CYP2A5 expression (catalytic activity and mRNA), while the cAMP and protein kinase A (PKA) stimulators dibutyryl-cAMP, forskolin and Sp-cAMPs caused up to 18-fold increases in the amount of CYP2A5 mRNA. Coadministration of PB and cAMP/PKA stimulating agents produced an additive inducing effect. The expression of CYP2A5, but not CYP2B10 or CYP1A1/2, in DBA/2 mice displayed a marked circadian rhythm, the level of expression being highest in the evening. These results suggest that among xenobiotic metabolizing CYP enzymes, CYP2A5 is uniquely upregulated by cAMP, possibly having the physiological function of priming the olfactory and digestive systems for nocturnal feeding.
Viitala
P
P
Department of Pharmacology and Toxicology, University of Oulu, FIN-90014 Oulu, Finland.
Posti
K
K
Lindfors
A
A
Pelkonen
O
O
Raunio
H
H
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D002940:Circadian Rhythm; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D065637:Cytochrome P-450 CYP2A6; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics*; D000072467:Cytochrome P450 Family 2; D019204:GTP-Binding Proteins / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D006899:Mixed Function Oxygenases / Q000096:biosynthesis / Q000235:genetics*; D010634:Phenobarbital / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D014444:Tyrosine Transaminase / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D003577:Cytochrome P-450 Enzyme System; D000242:Cyclic AMP; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585520:Cyp2a5 protein, mouse; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2; D014444:Tyrosine Transaminase; D017868:Cyclic AMP-Dependent Protein Kinases; D019204:GTP-Binding Proteins; D010634:Phenobarbital