The effect of isoniazid containing regimen on CYP2E1 during antituberculosis therapy.
Because isoniazid is a selective inducer of CYP2E1 and isoniazid-induced hepatotoxicity is believed to be due to activation of its metabolites by CYP450, this study was undertaken to determine the effect of isoniazid containing regimen on CYP2E1 in TB-patients. The activity of CYP2E1 in 11 newly diagnosed TB-patients (5 F, 6 M) was investigated before (day 0) and during (day 14) treatment for tuberculosis. CYP2E1 activity was measured using the plasma metabolic ratio (MR) of 6-hydroxy-chlorzoxazone to chlorzoxazone, while CYP2E1 quantity in the peripheral lymphocytes was measured using SDS-PAGE. By day 14 of anti-tuberculosis treatment, the activity of CYP2E1 was inhibited by 72% in 8 patients, but increased in 3 patients. The MR for the 8 patients was reduced from (Median & Range) 2.78 (1.1-21.5) on day 0, to 0.75 (0.4-1.22) on day 14, (P = 0.0006). Renal function was normal before and during the investigation. The detection of CYP2E1 by in peripheral lymphocytes was so variable that it could not be correlated with enzyme activity. Nevertheless, its detection in peripheral lymphocytes where normally is not resident indicates that CYP2E1 was induced by isoniazid. These results indicate that during treatment for tuberculosis with isoniazid containing regimen, CYP2E1 is induced but its activity is inhibited by isoniazid.
Walubo
Andrew
A
Department of Pharmacology, University of the Free State, South Africa. waluboa.md@mail.uovs.ac.za
Coetsee
Christa
C
Arti
Dhar
D
Du Plessis
J B
JB
D000328:Adult; D000995:Antitubercular Agents / Q000009:adverse effects* / Q000627:therapeutic use; D002753:Chlorzoxazone / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis*; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006801:Humans; D007538:Isoniazid / Q000009:adverse effects* / Q000627:therapeutic use; D008214:Lymphocytes / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D008875:Middle Aged; D009125:Muscle Relaxants, Central / Q000627:therapeutic use; D012307:Risk Factors; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy / Q000201:enzymology*
D000995:Antitubercular Agents; D009125:Muscle Relaxants, Central; D019392:Cytochrome P-450 CYP2E1; D002753:Chlorzoxazone; D007538:Isoniazid