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Regulation of Hepatic Drug-Metabolizing Enzyme Genes by Toll-Like Receptor 4 Signaling Is Independent of Toll-Interleukin 1 Receptor Domain-Containing Adaptor Protein

College of Pharmacy, University of Houston, Houston, Texas (R.G., T.G.); and Texas Children's Liver Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas (D.W., J.V., S.J.K.)

During inflammation, drug metabolism and clearance are altered due to suppression of hepatic drug-metabolizing enzyme (DME) genes and their regulatory nuclear receptors (NRs) [pregnane X receptor, constitutive androstane receptor, and retinoid X receptor (RXR)]. The bacterial endotoxin, lipopolysaccharide (LPS), induces expression of proinflammatory cytokines in the liver, which contribute to altered DME expression. LPS binds to the cell-surface receptor, Toll-like receptor 4 (TLR4), which initiates a signal transduction cascade, including recruitment of the Toll-interleukin 1 receptor domain-containing adaptor protein (TIRAP). However, the role of TLR4 and TIRAP in LPS-mediated regulation of hepatic DME gene expression is not known. Wild-type (C3HeB/FeJ), TLR4-mutant (C3H/HeJ), TIRAP^+/+, and TIRAP^-/- mice were injected i.p. with LPs. RNA levels of the major hepatic DME, Cyp3a11 and Ugt1a1, and the NRs were suppressed 60 to 70% by LPS in wild-type but not in the TLR4-mutant mice. The nuclear protein levels of RXR were reduced by LPS in wild-type but not in TLR4-mutant mice. Induction of hepatic cytokines (interleukin-1β, tumor necrosis factor-, and interleukin-6), c-Jun N-terminal kinase, and nuclear factor-B was blocked in TLR4-mutant mice. Surprisingly, LPS had the same effect on cytokines, kinases, NRs, and DME genes in livers of both TIRAP^+/+ and TIRAP^-/- mice, indicating that TIRAP is not essential for TLR4-mediated suppression of NRs and DMEs in liver. However, TIRAP^-/- mice have reduced serum cytokine expression compared with TIRAP^+/+ mice in response to LPS. This shows that although TIRAP mediates inflammatory responses induced by LPS, it is not essential in regulating LPS-mediated alterations of gene expression in liver.