Moderate hypothermia prevents cardiac arrest-mediated suppression of drug metabolism and induction of interleukin-6 in rats.
OBJECTIVE
Therapeutic hypothermia is being clinically used to reduce neurologic deficits after cardiac arrest (CA). Patients receiving hypothermia after CA receive a wide-array of medications. During hypothermia, drug metabolism is markedly reduced. Little, however, is known about the impact of hypothermia on drug metabolism after rewarming. The objective of this study was to examine the effect of CA and hypothermia on the functional regulation of two major drug metabolizing cytochrome P450 (CYP) isoforms.


METHODS
Laboratory investigation.


METHODS
University pharmacy school and animal research facility.


METHODS
Thirty-six male Sprague-Dawley rats.


METHODS
Hypothermia was induced via surface cooling in a rat CA model and maintained for 3 hrs. Animals were killed at 5 or 24 hrs and liver was analyzed for hepatic activity and mRNA expression of CYP3A2 and CYP2E1. Plasma interleukin-6 (IL-6) concentrations were determined. The effect of IL-6 on pregnane X receptor-mediated transcription of the rat CYP3A2 promoter was evaluated via luciferase reporter in HepG2 cells.


RESULTS
At 24 hrs after CA a decrease in CYP3A2 and CYP2E1 activity was observed, 55.7% +/- 12.8% and 46.8% +/- 29.7% of control, respectively (p < 0.01). CA decreased CYP3A2 mRNA (p < 0.05), but not CYP2E1 mRNA. Expression of other pregnane X receptor target enzymes and transporter genes were similarly down-regulated. CA also produced an approximately ten-fold increase in plasma IL-6. CA-mediated inhibition of CYP3A2 and CYP2E1 was attenuated by hypothermia, as was the increase in IL-6. Furthermore, IL-6 attenuated pregnane X receptor-mediated transcription of the CYP3A2 promoter.


CONCLUSIONS
CA produces CYP3A2 down-regulation at 24 hrs, potentially via IL-6 effects on pregnane X receptor-mediated transcription. Also, hypothermia attenuates the CA-mediated down-regulation, thereby normalizing drug metabolism after rewarming.
Tortorici
Michael A
MA
Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA.
Mu
Ying
Y
Kochanek
Patrick M
PM
Xie
Wen
W
Poloyac
Samuel M
SM
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D006323:Heart Arrest / Q000378:metabolism*; D007036:Hypothermia, Induced; D015850:Interleukin-6 / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D015850:Interleukin-6; D008565:Membrane Proteins; D004364:Pharmaceutical Preparations; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A