Tissue-specific alterations in the 6-hydroxylation of chlorzoxazone following traumatic brain injury in the rat.
Interest in the non-neuronal alterations following traumatic brain injury (TBI) has led to research evaluating hepatic metabolism following injury. Several models of injury demonstrate tissue-specific alterations in cytochrome P450 activity. This study examined tissue-specific alterations in cytochrome P450-mediated hydroxylation in the rat model of TBI. Male Sprague-Dawley rats received anesthesia alone, craniotomy, or craniotomy plus TBI. Rats were sacrificed at 24 and 48 h. Liver, kidney, and brain cortex microsomes were isolated. Total liver P450 content, 6-hydroxychlorzoxazone formation rate, and CYP2E1 protein were evaluated. In liver microsomes, spectral P450 was decreased to 86 +/- 5% (p < 0.05) of control at 24 h following injury, and 6-hydroxychlorzoxazone formation rate decreased to 74 +/- 18% of control (p < 0.05) at 48 h following injury. In kidney microsomes, 6-hydroxychlorzoxazone formation rate was increased to 154% of control (p < 0.01) 24 h following injury. 6-Hydroxychlorzoxazone formation rate was unaffected by TBI in brain cortical microsomes. The CYP2E1 inhibitor, 4-methylpyrazole, inhibited the formation of 6-hydroxychlorzoxazone in brain, kidney, and liver microsomes. These data demonstrate that tissue-specific alterations in 6-hydroxychlorzoxazone formation rate occur following TBI.
Poloyac
S M
SM
College of Pharmacy, Division of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, USA. poloyac+@pitt.edu
Perez
A
A
Scheff
S
S
Blouin
R A
RA
D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D001930:Brain Injuries / Q000201:enzymology / Q000378:metabolism*; D002753:Chlorzoxazone / Q000031:analogs & derivatives* / Q000378:metabolism*; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D000077604:Fomepizole; D006900:Hydroxylation; D007668:Kidney / Q000201:enzymology / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000201:enzymology / Q000378:metabolism; D009928:Organ Specificity; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D065691:Cytochrome P-450 CYP2E1 Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D011720:Pyrazoles; C039289:6-hydroxychlorzoxazone; D000077604:Fomepizole; D003577:Cytochrome P-450 Enzyme System; D019392:Cytochrome P-450 CYP2E1; D002753:Chlorzoxazone