Role of adrenoceptor-linked signaling pathways in the regulation of CYP1A1 gene expression.
Article Details
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Konstandi M, Kostakis D, Harkitis P, Marselos M, Johnson EO, Adamidis K, Lang MA
Role of adrenoceptor-linked signaling pathways in the regulation of CYP1A1 gene expression.
Biochem Pharmacol. 2005 Jan 15;69(2):277-87.
- PubMed ID
- 15627480 [ View in PubMed]
- Abstract
Alpha2-adrenoceptor agents as well as stress affect the activity of several hepatic monoxygenases including those related to CYP1A enzymes. This study was therefore designed to assess the role of central and/or peripheral catecholamines and, in particular, of adrenoceptors in the regulation of B(alpha)P-induced cytochrome CYP1A1 expression. In order to discriminate the role of central from that of peripheral catecholamines in the regulation of CYP1A1 induction, the effect of central and peripheral catecholamine depletion using reserpine versus only peripheral catecholamine depletion using guanethidine was assessed. By using selected agonists and antagonists, the role of alpha and beta-adrenoceptors in the regulation of CYP1A1 induction was evaluated. The results showed that the central catecholaminergic system has a negative regulatory effect on 7-ethoxyresorufin O-deethylase (EROD) inducibility by benzo(alpha)pyrene (B(alpha)P), and that this may be mediated via alpha1-, alpha2- and beta-adrenoceptors. Specifically, stimulation of alpha2-adrenoceptors with dexmedetomidine and blockade of alpha1- or beta-adrenoceptors with prazosin or propranolol respectively, resulted in a further increase of EROD inducibility. Adrenoceptors were found to be involved in the regulation of the CYP1A1 gene at mRNA level. Both, reduced noradrenaline release in central nervous system induced with dexmedetomidine and central catecholamine depletion, as well as blockade of central alpha1-adrenoceptors induced with prazosin, all were associated with up-regulation of CYP1A1 expression. In contrast, stimulation of central beta-adrenoceptors with isoprenaline resulted in a down-regulation of CYP1A1 expression. Our observations indicate that drugs, which stimulate or block adrenoceptors and catecholamine release may lead to complications in drug therapy and modulate the toxicity or carcinogenicity of drugs that are substrates for the CYP1A1.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Dexmedetomidine Cytochrome P450 1A1 Protein Humans UnknownInhibitorDetails Isoprenaline Cytochrome P450 1A1 Protein Humans UnknownInhibitorInducerDetails - Pharmaco-transcriptomics
Drug Drug Groups Gene Gene ID Change Interaction Chromosome Isoprenaline Approved Investigational CYP1A1 1543 downregulated Isoproterenol results in decreased expression of CYP1A1 mRNA 15q24.1 Prazosin Approved CYP1A1 1543 upregulated Prazosin results in increased expression of CYP1A1 mRNA 15q24.1