Phencyclidine Continuous Dosing Produces a Treatment Time- Dependent Regulation of Rat CYP2C11 Function, Protein Expression and mRNA Levels 1

ABSTRACT These studies determined the effects of continuous phencyclidine (PCP) administration on cytochrome P 450 2C11 (CYP2C11) function, protein expression and mRNA levels. Male Sprague-Dawley rats received s.c. PCP infusions (18 mg/kg/ day) for 1, 3, 10 or 20 days (n ϭ 4 per group). Control animals received saline infusions for 3 or 20 days. Livers were collected 24 hr postinfusion, a time when PCP was completely cleared from the animals. In microsomes from the 1-and 3-day PCP infusions, there was a significant decrease (P Ͻ .05) in CYP2C11 protein expression (61 and 46% of control values, respectively) and in CYP2C11-mediated metabolism of PCP to a reactive metabolite (36 and 41% of control values). Both protein expression and PCP metabolite formation had returned to normal by 10 days of continuous PCP infusion. CYP2C11 function (as measured by 2␣-OH testosterone formation) was decreased in the 1-, 3-and 10-day infused rats to 46, 28 and 45% of control values (P Ͻ .05). CYP2C11 function, expression and reactive PCP metabolite formation returned to normal after 20 days of PCP infusion. In contrast, CYP2C11 mRNA levels were decreased (P Ͻ .05) in liver tissue in PCP-treated rats from 1 to 20 days (43, 31, 37 and 47%, respectively). These data suggest that continuous PCP infusions initially decrease CYP2C11 function and protein expression by a pretranslational mechanism, but continued exposure to PCP leads to metabolic adaptation without the recovery of mRNA levels. Thus, chronic exposure to PCP can produce time-dependent regulation of CYP2C11-mediated metabolism of endogenous and exogenous compounds. PCP is metabolized by CYP enzymes to at least six major metabolites in mammals Chronic s.c. infusions of PCP for up to 20 days in normal male Sprague-Dawley rats produce complex time-and dosedependent changes in the in vitro metabolism of PC