Beta-adrenergic receptor modulation of the LPS-mediated depression in CYP1A activity in astrocytes.
CYP1A1 and 1A2, two important P450 isoforms in the brain that metabolize many endogenous and exogenous substrates, are downregulated during central nervous system (CNS) inflammation. The stimulation of beta-adrenergic receptors has been demonstrated to be anti-inflammatory in many cell types, leading us to hypothesize that stimulation of beta-adrenergic receptors could prevent the downregulation in CYP1A1 and 1A2 activity in an in vitro model of CNS inflammation. Isoproterenol, a general beta(1)/beta(2) receptor agonist, and clenbuterol, a specific beta(2) receptor agonist, were both able to prevent the LPS-induced downregulation in CYP1A1/2 activity in astrocytes. The involvement of beta-adrenergic receptors was confirmed using the general beta(1)/beta(2) receptor antagonist propranolol, which was able to abrogate the protection conferred by isoproterenol and clenbuterol in astrocytes treated with LPS. The isoproterenol and clenbuterol mediated protective effect on the LPS-induced downregulation in CYP1A activity was a cyclic AMP (cAMP) dependent process, since forskolin was able to mimic the protective effect. Isoproterenol and clenbuterol may also prevent the LPS-induced downregulation in CYP1A activity through changes in TNF alpha expression. Despite a slight reduction in the LPS-induced nuclear translocation of the p65 subunit of NF-kappa B, isoproterenol and clenbuterol had no effect on the DNA binding ability of this transcription factor, indicating that the beta-adrenergic protective effects on CYP1A activity occurred independent of changes in NF-kappa B activity. The results presented in this paper reveal that beta-adrenergic receptor stimulation can modulate cytochrome P450 activity in an in vitro model of CNS inflammation by a cAMP mediated pathway.
Abdulla
Dalya
D
Department of Pharmacology, Dalhousie University, Sir Charles Tupper Medical Building, Halifax, NS, Canada B3H 4H7.
Renton
Kenneth W
KW
D000818:Animals; D001253:Astrocytes / Q000201:enzymology*; D002478:Cells, Cultured; D002976:Clenbuterol / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D008070:Lipopolysaccharides; D016328:NF-kappa B; D011943:Receptors, Adrenergic, beta; D014409:Tumor Necrosis Factor-alpha; D000242:Cyclic AMP; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D007545:Isoproterenol; D002976:Clenbuterol