title: Phencyclidine continuous dosing produces a treatment time-dependent regulation of rat CYP2C11 function, protein expression and mRNA levels.
abstract: 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.
authors.affiliation: Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock 72205, USA.
authors.forename: S R
authors.initials: SR
authors.lastname: Shelnutt
authors.forename: L E
authors.initials: LE
authors.lastname: Cornett
authors.forename: S M
authors.initials: SM
authors.lastname: Owens
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D015152:Blotting, Northern; D015153:Blotting, Western; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D000072467:Cytochrome P450 Family 2; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010622:Phencyclidine / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D013739:Testosterone / Q000097:blood; D013997:Time Factors; D014284:Triiodothyronine / Q000097:blood
chemical_list: D018691:Excitatory Amino Acid Antagonists; D012333:RNA, Messenger; D014284:Triiodothyronine; D013739:Testosterone; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase; D010622:Phencyclidine