INACTIVATION OF CONSTITUTIVE HEPATIC CYTOCHROMES P450 BY PHENCYCLIDINE IN THE RAT

The purpose of this study was to determine whether phencyclidine (PCP) inhibits constitutive hepatic cytochrome P450 (CYP) isozymes when adm inistered to naive adult male Sprague-Dawley rats. Animals were pretre ated with PCP (25 mg/kglday for 2 days), killed 3 and 16 hr after the last dose, and liver microsomes prepared. The washed microsomes were t hen assayed for benzphetamine, methamphetamine (MA), and methylenediox ymethamphetamine (MDMA) N-demethylation together with MDMA demethylena tion and MA 4-hydroxylation activities, MDMA demethylenation (low subs trate concentration), MA 4-hydroxylation, and metoprolol alpha-hydroxy lation reactions, which are catalyzed by CYP2D isozymes, were reduced >74% 3 hr after the last PCP dose and were only partially restored 13 hr later. Benzphetamine and (-)-MDMA N-demethylation activities were r estored to control values 16 hr after the last dose. These results ind icate that PCP suppresses constitutive isozymes, including CYP2C11 and members of the CYP2D subfamily. The suppression of cytochromes P450 a ctivity by PCP in vivo is consistent with its in vitro actions found i n this and other studies, and demonstrates that alteration of CYP acti vity is another pharmacological effect of this compound.