Publikationsdatenbank

Confounding influence of tamoxifen in mouse models of Cre recombinase-induced gene activity or modulation (2018)

Art

Zeitschriftenartikel / wissenschaftlicher Beitrag

Autoren

Hammad, Seddik

Othman, Amnah (WE 2)

Meyer, Christoph

Telfah, Ahmad

Lambert, Joerg

Dewidar, Bedair

Werle, Julia

Nwosu, Zeribe Chike

Mahli, Abdo

Dormann, Christof

Gao, Yan

Gould, Kerry

Han, Mei

Yuan, Xiaodong

Gogiashvili, Mikheil

Hergenröder, Roland

Hellerbrand, Claus

Thomas, Maria

Ebert, Matthias Philip

Amasheh, Salah (WE 2)

Hengstler, Jan G

Dooley, Steven

Quelle

Archives of toxicology

Bandzählung: 92

Heftzählung: 8

Seiten: 2549 – 2561

ISSN: 0340-5761

Sprache

Englisch

Verweise

DOI: 10.1007/s00204-018-2254-4

Pubmed: 29974145

Kontakt

Institut für Veterinär-Physiologie

Oertzenweg 19 b
14163 Berlin
+49 30 838 62600
physiologie@vetmed.fu-berlin.de

Abstract / Zusammenfassung

Tamoxifen (TAM) is commonly used for cell type specific Cre recombinase-induced gene inactivation and in cell fate tracing studies. Inducing a gene knockout by TAM and using non-TAM exposed mice as controls lead to a situation where differences are interpreted as consequences of the gene knockout but in reality result from TAM-induced changes in hepatic metabolism. The degree to which TAM may compromise the interpretation of animal experiments with inducible gene expression still has to be elucidated. Here, we report that TAM strongly attenuates CCl4-induced hepatotoxicity in male C57Bl/6N mice, even after a 10 days TAM exposure-free period. TAM decreased (p < 0.0001) the necrosis index and the level of aspartate- and alanine transaminases in CCl4-treated compared to vehicle-exposed mice. TAM pretreatment also led to the downregulation of CYP2E1 (p = 0.0045) in mouse liver tissue, and lowered its activity in CYP2E1 expressing HepG2 cell line. Furthermore, TAM increased the level of the antioxidant ascorbate, catalase, SOD2, and methionine, as well as phase II metabolizing enzymes GSTM1 and UGT1A1 in CCl4-treated livers. Finally, we found that TAM increased the presence of resident macrophages and recruitment of immune cells in necrotic areas of the livers as indicated by F4/80 and CD45 staining. In conclusion, we reveal that TAM increases liver resistance to CCl4-induced toxicity. This finding is of high relevance for studies using the tamoxifen-inducible expression system particularly if this system is used in combination with hepatotoxic compounds such as CCl4.