title: Beta-adrenergic receptor modulation of the LPS-mediated depression in CYP1A activity in astrocytes.
abstract: 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.
authors.affiliation: Department of Pharmacology, Dalhousie University, Sir Charles Tupper Medical Building, Halifax, NS, Canada B3H 4H7.
authors.forename: Dalya
authors.initials: D
authors.lastname: Abdulla
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Renton
mesh_terms: 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
chemical_list: 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