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Head injury and cytochrome P-450 enzymes. Differential effect on mRNA and protein expression in the Fischer-344 rat
S M Toler1, A B Young, C J McClain
1College of Pharmacy, Division of Pharmacology and Experimental Therapeutics, University of Kentucky, Lexington 40536-0082.
Abstract:
Head trauma produces debilitating injuries that affect millions of people each year. Such injuries lead to a cascade of physiologic sequelae resulting in a hypercatabolic/hypermetabolic state. Current information describing changes in hepatic drug metabolism as a result of head trauma is limited. In this study, the effect of craniotomy and craniotomy plus cerebral percussive injury (impact) were investigated and compared with anesthesia control. Steady-state mRNA levels for CYP2C11 and CYP3A were suppressed to 50% of control values 24 hr following injury for the impact treatments. Craniotomy treatments also demonstrated a 50% decline in steady-state levels of mRNA for CYP3A 24 hr following injury. However, Western blot analysis of the CYP3A enzyme revealed no change at 6, 24, or 48 hr following injury. In addition, activities for 2 alpha- and 6 beta-testosterone hydroxylase did not differ from control values at any time point. Spectral analysis of total P-450 demonstrated a very small decline of 15% for the impact treatment 48 hr following injury. Total cytochrome P-450 content did not differ from control values at any other time point. Head injury produces a profound decline in steady-state mRNA concentrations for CYP2C11 and CYP3A that do not translate into altered protein expression.
Insights
Head trauma significantly reduces mRNA levels for drug-metabolizing enzymes CYP2C11 and CYP3A. However, this decrease in messenger RNA does not affect the actual protein levels or drug metabolism activity in the liver.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Head trauma is a common cause of severe injury, leading to a hypermetabolic state.
- Limited data exists on how head trauma impacts hepatic drug metabolism.
- Understanding these changes is crucial for managing patients with head injuries.
Purpose of the Study:
- To investigate the effects of craniotomy and impact-induced cerebral injury on hepatic drug metabolism.
- To compare these effects with anesthesia controls.
- To determine if changes in mRNA levels correlate with protein expression and enzyme activity.
Main Methods:
- Induction of craniotomy and cerebral percussive injury (impact) in a study model.
- Measurement of steady-state mRNA levels for CYP2C11 and CYP3A using quantitative techniques.
- Western blot analysis to assess CYP3A protein expression.
- Assay of testosterone hydroxylase activities and total cytochrome P-450 content.
Main Results:
- Impact treatments significantly suppressed CYP2C11 and CYP3A mRNA levels by 50% at 24 hours post-injury.
- Craniotomy alone also reduced CYP3A mRNA levels by 50% at 24 hours.
- No significant changes in CYP3A protein expression, testosterone hydroxylase activity, or total cytochrome P-450 content were observed at any time point.
Conclusions:
- Head injury causes a substantial decrease in CYP2C11 and CYP3A mRNA concentrations.
- These alterations in mRNA do not lead to corresponding changes in hepatic enzyme protein expression or activity.
- Hepatic drug metabolism appears resilient to acute changes in mRNA levels following head trauma.