Role of CYP2E1 and saturation kinetics in the bioactivation of thioacetamide: Effects of diet restriction and phenobarbital
- Department of Toxicology, College of Pharmacy, University of Louisiana Monroe, 700 University Avenue, Sugar Hall 306, Monroe, LA 71209-0470 (United States)
- Arkansas Children's Nutrition Center, Little Rock, AR (United States)
- Division of Basic Pharmaceutical Sciences (R.A.H.), College of Pharmacy, University of Louisiana Monroe, Monroe, LA (United States)
- Pathology Associates International, National Center for Toxicological Research, Jefferson, AR (United States)
Thioacetamide (TA) undergoes saturation toxicokinetics in ad libitum (AL) fed rats. Diet restriction (DR) protects rats from lethal dose of TA despite increased bioactivation-mediated liver injury via CYP2E1 induction. While a low dose (50 mg TA/kg) produces 6-fold higher initial injury, a 12-fold higher dose produces delayed and mere 2.5-fold higher injury. The primary objective was to determine if this less-than-expected increase in injury is due to saturation toxicokinetics. Rats on AL and DR for 21 days received either 50 or 600 mg TA/kg i.p. T {sub 1/2} and AUCs for TA and TA-S-oxide were consistent with saturable kinetics. Covalent binding of {sup 14}C-TA-derived-radiolabel to liver macromolecules after low dose was 2-fold higher in DR than AL rats. However, following lethal dose, no differences were found between AL and DR. This lack of dose-dependent response appears to be due to saturation of bioactivation at the higher dose. The second objective was to investigate the effect of phenobarbital pretreatment (PB) on TA-initiated injury following a sub-lethal dose (500 mg/kg). PB induced CYP2B1/2 {approx} 350-fold, but did not increase covalent binding of {sup 14}C-TA, TA-induced liver injury and mortality, suggesting that CYP2B1/2 has no major role in TA bioactivation. The third objective was to investigate the role of CYP2E1 using cyp2e1 knockout mice (KO). Injury was assessed over time (0-48 h) in wild type (WT) and KO mice after LD{sub 100} dose (500 mg/kg) in WT. While WT mice exhibited robust injury which progressed to death, KO mice exhibited neither initiation nor progression of injury. These findings confirm that CYP2E1 is responsible for TA bioactivation.
- OSTI ID:
- 20976871
- Journal Information:
- Toxicology and Applied Pharmacology, Vol. 219, Issue 1; Other Information: DOI: 10.1016/j.taap.2006.11.036; PII: S0041-008X(06)00461-3; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
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