Comparison of acetaminophen toxicity in primary hepatocytes isolated from transgenic mice with different appolipoprotein E alleles
Language English Country Poland Media print
Document type Comparative Study, Journal Article, Research Support, Non-U.S. Gov't
PubMed
26769836
Knihovny.cz E-resources
- MeSH
- Alleles MeSH
- Apolipoproteins E genetics MeSH
- Gene Expression drug effects MeSH
- NF-E2-Related Factor 2 genetics MeSH
- Genotype MeSH
- Glutathione metabolism MeSH
- Hepatocytes drug effects metabolism physiology MeSH
- Cells, Cultured MeSH
- Membrane Potential, Mitochondrial drug effects MeSH
- Lipid Metabolism drug effects MeSH
- Mice, Inbred C57BL MeSH
- Mice, Transgenic MeSH
- Analgesics, Non-Narcotic toxicity MeSH
- Oxidative Stress drug effects MeSH
- Acetaminophen toxicity MeSH
- Reactive Oxygen Species metabolism MeSH
- Animals MeSH
- Check Tag
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Comparative Study MeSH
- Names of Substances
- Apolipoproteins E MeSH
- NF-E2-Related Factor 2 MeSH
- Glutathione MeSH
- Analgesics, Non-Narcotic MeSH
- Acetaminophen MeSH
- Reactive Oxygen Species MeSH
The nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor, important for combating electrophilic and oxidative stress in the liver and other organs. This encompasses detoxification of hepatotoxic drugs, including acetaminophen (APAP). Recently, an association between apolipoprotein E (ApoE) genotype and Nrf2 expression was described. We compared the toxicity of APAP on primary culture hepatocytes isolated from transgenic mice carrying two different human ApoE alleles and wild-type controls. The cells were exposed to APAP in concentrations from 0.5 to 4 mM for up to 24 hours. APAP led to a dose-dependent hepatotoxicity from 1 mM after 16 h exposure in all mice tested. The toxicity was higher in hepatocytes isolated from both transgenic strains than in wild-type controls and most pronounced in ApoE3 mice. Concurrently, there was a decline in mitochondrial membrane potential, especially in ApoE3 hepatocytes. The formation of reactive oxygen species was increased after 24 hours with 2.5 mM APAP in hepatocytes of all strains tested, with the highest increase being in the ApoE3 genotype. The activity of caspases 3 and 7 did not differ among groups and was minimal after 24 hour incubation with 4 mM APAP. We observed higher lipid accumulation in hepatocytes isolated from both transgenic strains than in wild-type controls. The expression of Nrf2-dependent genes was higher in ApoE3 than in ApoE4 hepatocytes and some of these genes were induced by APAP treatment. In conclusion, transgenic mice with ApoE4 and ApoE3 alleles displayed higher susceptibility to acute APAP toxicity in vitro than wild-type mice. Of the two transgenic genotypes tested, ApoE3 allele carriers were more prone to injury.
