Regulation of drug metabolizing enzymes in inflammation: Role of the Toll‐like receptor 4 signaling pathway

Abstract

Background: During inflammation, drug metabolism and clearance is altered due to suppression of drug metabolizing enzymes (DMEs), and their regulatory nuclear receptors (NRs: PXR, CAR and RXRα). Inflammatory responses are mediated by Toll-like receptors (TLRs) which suppress hepatic genes by cytokine-dependent mechanism. TLR-signaling involves the adaptor protein, TIRAP, whose role in TLR-mediated regulation of hepatic DMEs is unknown. We hypothesize that inflammation-mediated suppression of hepatic DMEs involves TLR4 and the adaptor, TIRAP. Methods: Wild-type (C3HeB/FeJ), TLR4-mutant (C3H/HeJ), TIRAP+/+ and TIRAP−/− mice were injected intraperitoneally with the TLR4 ligand, lipopolysaccharide (LPS, 2 μg/g). Hepatic RNA and proteins were analyzed by real-time PCR and western blotting, respectively. Results: LPS treatment resulted in ~75% down-regulation of the major hepatic DME, Cyp3a11, and the NRs in wild-type, but not TLR4-mutant mice. Induction of cytokines (IL-1β, TNFα and IL-6) was blocked in TLR4-mutant mice. LPS had the same effect in TIRAP+/+ and TIRAP−/− mice, indicating that TIRAP is not involved in TLR4-mediated suppression of Cyp3a11. LPS treatment suppressed Cyp3a11 and NRs in hepatocytes isolated from wild-type, but not mutant mice. Conclusions: Activation of TLR4 in macrophages as well as hepatocytes suppresses Cyp3a11 gene expression by TIRAP-independent pathway.