cAMP mediated upregulation of CYP2A5 in mouse hepatocytes

CYP2A5 is induced by a large number of chemicals including some cAMP modifi ers. In a primary hepatocyte model, stimulation of the cAMP signal transduc tion pathway by glucagon and isoproterenol, acting via specific G-protein c oupled plasma membrane receptors, produced up to 17-fold increases in the m arker 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 CYP2 A5 expression (catalytic activity and mRNA), while the cAMP and protein kin ase 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 expre ssion of CYP2A5, but not CYP2B10 or CYP1A1/2, in DBA/2 mice displayed a mar ked circadian rhythm, the level of expression being highest in the evening. These results suggest that among xenobiotic metabolizing CYP enzymes, CYP2 A5 is uniquely upregulated by cAMP, possibly having the physiological funct ion of priming the olfactory and digestive systems for nocturnal feeding. ( C) 2001 Academic Press.