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Taxol alters gene expression of drug metabolizing enzymes by TLR4 dependent mechanism in vitro
Author(s) -
Mallick Pankajini,
Shah Pranav,
Ghose Romi
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.894.8
Subject(s) - tlr4 , pregnane x receptor , tlr2 , receptor , pharmacology , in vitro , tumor necrosis factor alpha , drug , biology , chemistry , transcription factor , biochemistry , gene , immunology , nuclear receptor
Toll‐like receptors (TLRs) are pattern recognition receptors that are key components of the innate immune system. We have shown activation of TLR2 and TLR4 leads to down‐regulation of drug metabolizing enzymes (DMEs). Recently, TLR agonists are increasingly used in poly‐pharmacy settings. These medications can alter DME expression and cause drug‐drug interactions with co‐administered drugs. Taxol is a ligand for TLR4 and pregnane X receptor (PXR). Therefore, taxol may (a) increase DME expression by activating PXR and/or (b) reduce DME expression by activating TLR4. We hypothesize that the effect of taxol on DMEs will be higher in the absence of TLR4. Primary hepatocytes isolated from adult male C57BL/6 mice were treated with taxol (1–20μM). RNA was analyzed by real‐time PCR. To determine the role of TLR4, the cells were incubated with a TLR4 inhibitor, TAK‐242 (1μM) for 1h, followed by treatment with taxol for 24h. Taxol induces Cyp3a11 (~9–19 fold), Cyp2b10 (~7–8 fold) and Ugt1a1 (~3–4 fold). Taxol significantly induced cytokines interleukin (IL)1‐β, IL‐6 and tumor necrosis factor (TNF)α. Ugt1a1 induction by taxol significantly increased (~2.5 fold) upon treatment with TAK‐242 but it did not affect the induction of Cyp3a11 and Cyp2b10 by taxol. The results indicate that TLR4 has a role in regulating expression of Ugt1a1 by taxol in vitro. Thus TLR4 may mediate drug interactions between taxol and Ugt1a1 substrates