Evidence of α2-adrenoceptor involvement in B[α]P induction processes of drug-metabolizing enzymes: the effect of stress

Abstract

Central to the appropriate regulation of behavioral and physiological changes induced by stress are the noradrenergic neuronal systems which have been implicated in a large number of stress-induced pathophysiological states. Endoplasmic reticulum-bound cytochromes (CYPs) play a crucial role in drug metabolism, resulting in deactivation or formation of reactive derivatives. In turn, these products may be responsible for the chemotherapeutic, mutagenic or carcinogenic properties of the parent compound. The present study assesses the effect of a specific alpha2- adrenoceptor agonist, dexmedetomidine (DEXT), on stress-induced modification of cytochrome activity in rats using a restraint stress model. The results indicated that activation of the alpha2-adrenoceptor with DEXT did not alter basal hepatic methoxyresorufin 7-dealkylase (MROD). On the other hand, it appeared to enhance MROD in benzo[alpha]pyrene (B[alpha]P) treated animals. Of interest was the finding that stress blocked DEXT-induced MROD enhancement in B[alpha]P- treated rats. In addition, DEXT had no effect on basal hepatic pentoxyresorufin 7-dealkylase (PROD), while it further enhanced the strong induction by B[alpha]P. Stress was also found to block this effect. Hepatic ethoxyresorufin 7-dealkylase (EROD) activity was strongly increased by B[alpha]P; this effect was enhanced by DEXT. In contrast, the DEXT enhanced induction was further strengthened by stress. These findings suggest that alpha2-adrenoceptors may modulate the induction of cytochromes CYP1A1, 1A2 and 2B1 by B[alpha]P in rats and that stress may modify this process. In particular, stress may regulate the inducibility of P4501A1 activity by B[alpha]P via mechanisms related to alpha2-adrenoceptors.

Predominant Role of Peripheral Catecholamines in the Stress‐Induced Modulation of CYP1A2 Inducibility by Benzo(α)pyrene

“…Previous data have shown that catecholamines and adrenoceptors have been implicated in the modulation of hepatic enzymatic activities [12] (fig. 1).…”

“…Previous studies have shown that psychological and physical stress is involved in the regulation of CYP1A1 and CYP1A2 [11][12][13][14]. In particular, repeated restraint stress, an experimental model of psychological and physical stress [15,16], has been found to modify both the constitutive and benzo( α )pyreneinduced CYP1A2-dependent 7-methoxyresorufin-O-dealkylase (MROD) activity [12,13].…”

“…In particular, repeated restraint stress, an experimental model of psychological and physical stress [15,16], has been found to modify both the constitutive and benzo( α )pyreneinduced CYP1A2-dependent 7-methoxyresorufin-O-dealkylase (MROD) activity [12,13]. Constitutive MROD was suppressed under restraint stress [13], while MROD inducibility by benzo( α )pyrene was increased [12,13]. The mechanisms underlying the stress effect on benzo( α )pyrene-induced CYP1A have not yet been clarified.…”

“…In particular, the up-regulating effect of stress on CYP1A1 induction appears to be mediated mainly by peripheral catecholamines, while central noradrenergic pathways appear to be indirectly involved in a down-regulating effect of stress [14]. We hypothesize that the stress-induced release of noradrenaline may play a critical role in the regulation of the genes under investigation during stress [11,12,17,25,26].…”

“…In particular, α 2 -adrenoceptors may modulate the induction of CYP1A enzymes by benzo( α )pyrene [12]. The consequences of this The involvement of hypothalamic-pituitary-GH, -PRL and -thyroid hormone axes in the regulation of CYP1A2 is also indicated.…”