Evidence of alpha 2-adrenoceptor involvement in B[alpha]P induction processes of drug-metabolizing enzymes: the effect of stress

Central to the appropriate regulation of behavioral and physiological chang es 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, mutag enic or carcinogenic properties of the parent compound. The present study a ssesses the effect of a specific alpha 2- adrenoceptor agonist, dexmedetomi dine (DEXT), on stress-induced modification of cytochrome activity in rats using a restraint stress model. The results indicated that activation of th e alpha 2-adrenoceptor with DEXT did not alter basal hepatic methoxyresoruf in 7-dealkylase (MROD). On the other hand, it appeared to enhance MROD in b enzo[alpha]pyrene (B[alpha]P) treated animals. Of interest was the finding that stress blocked DEXT-induced MROD enhancement in B[alpha]P- treated rat s. In addition, DUCT had no effect on basal hepatic pentoxyresorufin 7-deal kylase (PROD), while it further enhanced the strong induction by B[alpha]P. Stress was also found to block this effect. Hepatic ethoxyresorufin 7-deal kylase (EROD) activity was strongly increased by B[alpha]P; this effect was enhanced by DEXT. In contrast, the DEXT enhanced induction was further str engthened by stress. These findings suggest that alpha 2-adrenoceptors may modulate the induction of cytochromes CYP1A1, 1A2 and 2B1 by B[alpha]P in r ats and that stress may modify this process. In particular, stress may regu late the inducibility of P4501A1 activity by B[alpha]P via mechanisms relat ed to alpha 2-adrenoceptors.