Hepatic cytochrome P450 2E1 activity in nonalcoholic fatty liver disease.
BACKGROUND
Nonalcoholic fatty liver disease (NAFLD) is a worldwide phenomenon spanning all the continents. The pathogenesis of NAFLD has not been completely elucidated. One hypothesis is that hepatic cytochrome P450 2E1 (CYP2E1) plays an important role in increasing the lipid peroxidation and oxidative stress in NAFLD.


OBJECTIVE
The aim of the present study was to examine hepatic CYP2E1 activity in patients with NAFLD.


METHODS
Healthy subjects were included. After an overnight fasting, the subjects were orally administered 400 mg chlorzoxazone (CHZ) and serial blood samples were collected at 0 (predose), 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6 and 8 hours after dosing. For patients with NAFLD, plasma samples were collected at 0 (predose), 1.5, 2, 2.5 and 3 hours after dosing. Plasma CHZ and 6-hydroxychlorzoxazone (6-OH-CHZ) was assayed by reversed-phase high-performance liquid chromatography (HPLC) with UV detector. Hepatic CYP2E1 activity was calculated by using concentration ratio of 6-OH-CHZ / CHZ.


RESULTS
High concentration levels of CHZ and 6-OH-CHZ in healthy subjects were found between 1.5 to 3 hours after the dose. At 1.5 to 3 hours, the concentration ratio of 6-OH-CHZ / CHZ of patients with NAFLD seemed to be more than of healthy subjects. The time point which showed most different was 2.5 hours. (0.40 +/- 0.27 vs. 0.25 +/- 0.12 microg/ml, respectively, p = 0.10).


CONCLUSIONS
Although significant difference of the concentration ratio of 6-OH-CHZ / CHZ between the two groups was not exhibited, the data demonstrated the possibility of the increasing hepatic CYP2E1 activity in NAFLD. The concentration ratio of 6-OH-CHZ / CHZ at the point 2.5 hours may be the best index for measuring hepatic CYP2E1 activity in NAFLD.
Prompila
Nantaporn
N
Department of Pharmacology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
Wittayalertpanya
Supeecha
S
Komolmit
Piyawat
P
D000328:Adult; D016022:Case-Control Studies; D002753:Chlorzoxazone / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D019392:Cytochrome P-450 CYP2E1 / Q000032:analysis / Q000378:metabolism*; D005234:Fatty Liver / Q000201:enzymology*; D005260:Female; D006801:Humans; D015227:Lipid Peroxidation; D008099:Liver / Q000201:enzymology*; D008297:Male; D009125:Muscle Relaxants, Central / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D018384:Oxidative Stress; D010865:Pilot Projects
D009125:Muscle Relaxants, Central; C039289:6-hydroxychlorzoxazone; D019392:Cytochrome P-450 CYP2E1; D002753:Chlorzoxazone