Beta-adrenergic receptor modulation of the LPS-mediated depression in CYP1A activity in astrocytes.

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Abdulla D, Renton KW

Beta-adrenergic receptor modulation of the LPS-mediated depression in CYP1A activity in astrocytes.

Biochem Pharmacol. 2005 Mar 1;69(5):741-50. doi: 10.1016/j.bcp.2004.11.020. Epub 2005 Jan 13.

PubMed ID

15710352 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Clenbuterol	Cytochrome P450 1A1	Protein	Humans	Unknown	Substrate	Details