Benzo(alpha)pyrene-induced up-regulation of CYP1A2 gene expression: role of adrenoceptor-linked signaling pathways.
CYP1A2, a principal catalyst for metabolism of various therapeutic drugs and carcinogens, among others, is in part regulated by the stress response. This study was designed to assess whether catecholamines and in particular adrenergic receptor-dependent pathways, modulate benzo(alpha)pyrene (B(alpha)P)-induced hepatic CYP1A2. To distinguish between the role of central and peripheral catecholamines in the regulation of CYP1A2 induction, the effect of central and peripheral catecholamine depletion using reserpine was compared to that of peripheral catecholamine depletion using guanethidine. The effects of peripheral adrenaline and L-DOPA administration were also assessed. The results suggest that alterations in central catecholamines modulate 7-methoxyresorufin O-demethylase activity (MROD), CYP1A2 mRNA and protein levels in the B(alpha)P-induced state. In particular, central catecholamine depletion, dexmedetomidine-induced inhibition of noradrenaline release and blockade of alpha(1)-adrenoceptors with prazosin, up-regulated CYP1A2 expression. Phenylephrine and dexmedetomidine-induced up-regulation may be mediated, in part, via peripheral alpha(1)- and alpha(2)-adrenoceptors, respectively. On the other hand, the L-DOPA-induced increase in central dopaminergic activity was not followed by any change in the up-regulation of CYP1A2 expression by B(alpha)P. Central noradrenergic systems appeared to counteract up-regulating factors, most likely via alpha(1)- and alpha(2)-adrenoceptors. In contrast, peripheral alpha- and beta-adrenoceptor-related signaling pathways are linked to up-regulating processes. The findings suggest that drugs that bind to adrenoceptors or affect central noradrenergic neurotransmission, as well as factors that challenge the adrenoceptor-linked signaling pathways may deregulate CYP1A2 induction. This, in turn, may result in drug-therapy and drug-toxicity complications.
Konstandi
Maria
M
Department of Pharmacology Medical School, University of Ioannina, GR-451 10, Greece. mkonstan@cc.uoi.gr
Kostakis
Dimitris
D
Harkitis
Panagiotis
P
Johnson
Elizabeth O
EO
Marselos
Marios
M
Adamidis
Konstadinos
K
Lang
Matti A
MA
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001564:Benzo(a)pyrene / Q000494:pharmacology*; D002395:Catecholamines / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics; D003580:Cytochromes; D020927:Dexmedetomidine / Q000494:pharmacology; D004837:Epinephrine / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006145:Guanethidine / Q000494:pharmacology; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D010088:Oxidoreductases / Q000096:biosynthesis / Q000235:genetics; D011224:Prazosin / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011941:Receptors, Adrenergic / Q000378:metabolism*; D012110:Reserpine / Q000494:pharmacology; D015398:Signal Transduction; D013565:Sympatholytics / Q000494:pharmacology; D015854:Up-Regulation
D018759:Adrenergic Uptake Inhibitors; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D002395:Catecholamines; D003580:Cytochromes; D012333:RNA, Messenger; D011941:Receptors, Adrenergic; D013565:Sympatholytics; D001564:Benzo(a)pyrene; D007980:Levodopa; D020927:Dexmedetomidine; D012110:Reserpine; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; C076307:methoxyresorufin-O-demethylase; C017170:Cyp1a2 protein, rat; D019388:Cytochrome P-450 CYP1A2; D011224:Prazosin; D004837:Epinephrine; D006145:Guanethidine