THE CHRONIC ADMINISTRATION OF NICOTINE INDUCES CYTOCHROME-P450 IN RAT-BRAIN

The objective of these studies was to determine whether chronic admini stration of nicotine altered the cytochrome P450 (P450) monooxygenase system in rat brain. Male Sprague-Dawley rats received injections of n icotine bitartrate (1.76 mg/kg, s.c., twice daily for 10 days), and to tal cytochrome P450 content, the activity of NADPH-cytochrome c reduct ase, and the activities and relative abundance of P4502B1 and P4502B2 (P4502B1/2) were determined in microsomal fractions from rat brain. Th e content of P450 increased significantly (p < 0.02) in all brain regi ons examined from nicotine-injected rats; the largest increase (208% o f control) was in frontal cortex and the smallest increase (122% of co ntrol) in cerebellum. The activity of NADPH-cytochrome c reductase was unaltered by nicotine administration. Benzyloxyresorufin O-dealkylase (BROD) and pentoxyresorufin O-dealkylase (PROD) activities, mediated by P4502B1/2, increased significantly (p < 0.02) following nicotine ad ministration; the largest increase (213-227% of control) was in fronta l cortex. Western blots of microsomal proteins indicated that the incr ease in enzymatic activity was associated with an increase in content of P4502B1/2 immunoreactive proteins. In contrast to brain, total P450 content, activities of NADPH-cytochrome c reductase, BROD, and PROD, and levels of P4502B1/2 immunoreactive proteins in liver were unaffect ed by chronic nicotine administration. Results indicate that chronic n icotine administration regulates the expression of P4502B1/2 in brain and that at the dose schedule used this effect occurs without a demons trable effect on the hepatic P450 monooxygenase system.