Role of CYP2E1 in thioacetamide-induced mouse hepatotoxicity
Previous experiments showed that treatment of mice and rats with thioacetamide (TAA) induced liver cell damage, fibrosis and/or cirrhosis, associated with increased oxidative stress and activation of hepatic stellate cells. Some experiments suggest that CYP2E1 may be involved in the metabolic activa...
Saved in:
Published in | Toxicology and applied pharmacology Vol. 228; no. 3; pp. 295 - 300 |
---|---|
Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
San Diego, CA
Elsevier Inc
01.05.2008
Elsevier |
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | Previous experiments showed that treatment of mice and rats with thioacetamide (TAA) induced liver cell damage, fibrosis and/or cirrhosis, associated with increased oxidative stress and activation of hepatic stellate cells. Some experiments suggest that CYP2E1 may be involved in the metabolic activation of TAA. However, there is no direct evidence on the role of CYP2E1 in TAA-mediated hepatotoxicity. To clarify this, TAA-induced hepatotoxicity was investigated using
Cyp2e1-null mice. Male wild-type and
Cyp2e1-null mice were treated with TAA (200 mg/kg of body weight, single, i.p.) at 6 weeks of age, and hepatotoxicity examined 24 and 48 h after TAA treatment. Relative liver weights of
Cyp2e1-null mice were significantly different at 24 h compared to wild-type mice (
p
<
0.01). Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) in
Cyp2e1-null mice were significantly different at both time points compared to wild-type mice (
p
<
0.01). Histopathological examination showed
Cyp2e1-null mice represented no hepatototoxic lesions, in clear contrast to severe centriobular necrosis, inflammation and hemorrhage at both time points in wild-type mice. Marked lipid peroxidation was also only limited to wild-type mice (
p
<
0.01). Similarly, TNF-α, IL-6 and glutathione peroxidase mRNA expression in
Cyp2e1-null mice did not significantly differ from the control levels, contrasting with the marked alteration in wild-type mice (
p
<
0.01). Western blot analysis further revealed no increase in iNOS expression in
Cyp2e1-null mice. These results reveal that CYP2E1 mediates TAA-induced hepatotoxicity in wild-type mice as a result of increased oxidative stress. |
---|---|
Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0041-008X 1096-0333 |
DOI: | 10.1016/j.taap.2007.11.010 |