Abstract
Background:Altered expression of drug metabolizing enzymes (DMEs) in inflammation can affect the metabolism and toxicity of drugs. It is known that inflammatory responses are induced in immune cells by Lipopolysaccahride (LPS) and Lipoteichoic acid (LTA), derived from gram −ve and gram +ve bacteria, respectively. We reported that LPS modulates gene expression of hepatic DMEs and their regulatory nuclear receptors (NRs: PXR, CAR and RXRα) by activating Toll‐like receptor (TLR) 4 signaling pathway. We hypothesize that LTA can modulate NR and DME gene expression by activating the TLR2 signaling pathway. Methods: Adult male C57BL/6 mice were i.p. injected with 6 μg/g bw LTA or saline. Livers were harvested and RNA and proteins were analyzed by real‐time PCR and western blotting, respectively.Results:LTA treatment for 2h resulted in ∼80% suppression of CAR and target DME genes, Cyp2b10, Cyp2a4 and Sultn. The NR, PXR, and the main phase 1 DME, Cyp3a11 were reduced ∼70% by 4–8 h of LTA treatment. Nuclear protein levels of RXRα were reduced in LTA‐treated mice. LTA injection induced cytokine production and cell‐signaling components in the liver. The effects of LTA on NRs, DMEs, cytokines and cell‐signaling pathways were blocked in TLR2−/− mice, indicating that the effects of LTA on hepatic genes were mediated by TLR2.Conclusions:TLR2 is involved in regulating DME gene expression during induction of inflammation by LTA.
Published Version
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