Head injury and cytochrome P-450 enzymes. Differential effect on mRNA and protein expression in the Fischer-344 rat.
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.
Toler
S M
SM
College of Pharmacy, Division of Pharmacology and Experimental Therapeutics, University of Kentucky, Lexington 40536-0082.
Young
A B
AB
McClain
C J
CJ
Shedlofsky
S I
SI
Bandyopadhyay
A M
AM
Blouin
R A
RA
D000818:Animals; D015153:Blotting, Western; D001930:Brain Injuries / Q000201:enzymology* / Q000378:metabolism / Q000503:physiopathology; D003399:Craniotomy; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004195:Disease Models, Animal; D005069:Evaluation Studies as Topic; D015971:Gene Expression Regulation, Enzymologic; D015850:Interleukin-6 / Q000032:analysis; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008099:Liver / Q000201:enzymology; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344
D015850:Interleukin-6; D007527:Isoenzymes; D011506:Proteins; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System