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首页> 外文期刊>Biochemical Pharmacology >Role of adrenoceptor-linked signaling pathways in the regulation of CYP1A1 gene expression.
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Role of adrenoceptor-linked signaling pathways in the regulation of CYP1A1 gene expression.

机译：肾上腺素受体相关的信号通路在CYP1A1基因表达调控中的作用。

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摘要

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.
机译：Alpha2-肾上腺素能受体药物以及应激会影响几种肝单加氧酶的活性，包括那些与CYP1A酶相关的酶。因此，本研究旨在评估中枢和/或外周儿茶酚胺，尤其是肾上腺素受体在调节BαP诱导的细胞色素CYP1A1表达中的作用。为了区分中枢和外围儿茶酚胺在调节CYP1A1诱导中的作用，评估了利血平对中枢和外周儿茶酚胺消耗的影响与仅对胍胍对外周和儿茶酚胺消耗的影响。通过使用选定的激动剂和拮抗剂，评估了α和β-肾上腺素受体在CYP1A1诱导中的调节作用。结果表明，中央儿茶酚胺能系统对苯并α-py（BαP）诱导的7-乙氧基间苯二酚O-脱乙基酶（EROD）具有负调节作用，并且这可能是通过α1-，α2-介导的和β肾上腺素受体。具体地，分别用右美托咪定刺激α2-肾上腺素受体和用哌唑嗪或普萘洛尔分别阻断α1-或β-肾上腺素受体导致了EROD诱导性的进一步增加。发现肾上腺素受体在mRNA水平上参与CYP1A1基因的调节。右美托咪定和中枢儿茶酚胺耗竭诱导的中枢神经系统去甲肾上腺素释放减少，以及哌唑嗪诱导的中枢α1-肾上腺素受体阻滞，均与CYP1A1表达上调有关。相反，用异丙肾上腺素刺激中枢β-肾上腺素受体导致CYP1A1表达下调。我们的观察结果表明，刺激或阻断肾上腺素能受体和儿茶酚胺释放的药物可能导致药物治疗中的并发症，并调节作为CYP1A1底物的药物的毒性或致癌性。

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