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 2α-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.
Footnotes
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Send reprint requests to: Dr. S. Michael Owens, Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Slot 611, 4301 West Markham Street, Little Rock, AR 72205.
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↵1 This work was supported by National Institute on Drug Abuse Grant DA 04136, a Research Scientist Development Award (K02 DA 00110) to S.M.O. and a National Research Service Award to S.R.S. (F31 DA 05607). A preliminary report of these studies was presented at the annual meeting of the College on Problems of Drug Dependence127: 1996.
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↵2 Current address: Department of Pediatrics, Arkansas Children’s Hospital, Little Rock, AR, 72202.
- Abbreviations:
- CYP
- cytochrome P450
- MK-801
- (+)-methyl-10,11-dihydro-5H-dibenzo[a, d]cyclohepten-5,10-imine
- NMDA
- N-methyl-d-aspartate
- PCP
- phencyclidine
- SDS-PAGE
- sodium dodecyl sulfate-polyacrylamide gel electrophoresis
- T3
- triiodothyronine
- TLC
- thin-layer chromatography
- 2α-OH
- 4-androsten-2α,17β-diol-3-one
- 6α-OH
- 4-androsten-6α,17β-diol-3-one
- Received July 23, 1996.
- Accepted December 30, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
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