Phencyclidine continuous dosing produces a treatment time-dependent regulation of rat CYP2C11 function, protein...

These studies determined the effects of continuous phencyclidine (PCP) administration on cytochrome P450 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 = 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 < .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 2alpha-OH testosterone formation) was decreased in the 1-, 3- and 10-day infused rats to 46, 28 and 45% of control values (P < .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 < .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.