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

Abstract

ABSTRACT: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 ϳ60 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-1␤, tumor necrosis factor-␣, and interleukin-6), c-Jun N-terminal kinase, and nuclear factor-〉 was blocked in TLR4-mutant mice. Surprisingly, LPS had the same effect on cytokines, kinases, NRs, and DME genes in livers of both TIRAP

Role of Constitutive Androstane Receptor in Toll-Like Receptor-Mediated Regulation of Gene Expression of Hepatic Drug-Metabolizing Enzymes and Transporters

“…Role of CAR in Regulation of DME Genes through TLR2 and TLR4 177 at ASPET Journals on May 12, 2018 dmd.aspetjournals.org Downloaded from CAR gene expression (;70%) at 16 hours (Ghose et al, 2008(Ghose et al, , 2009. LTA administration led to downregulation of Cyp3a11, Cyp2a4, Cyp2b10, Ugt1a1, Sultn, and Mrp2 genes in CAR +/+ mice at time points ranging from 4 to 16 hours, as we have seen previously (Ghose et al, 2009).…”

“…Several studies have shown that downregulation of PXR and CAR genes was associated with decreased DME and transporter gene expression (Beigneux et al, 2000(Beigneux et al, , 2002Ghose et al, 2004Ghose et al, , 2008Ghose et al, , 2009. We have also shown that there is preferential suppression of CAR and its target hepatic genes on administration of LTA (Ghose et al, 2009).…”

“…Our results show that the induction of cytokines in the liver by LPS and LTA occurred to different extents. LTA administration led to ;80-, 35-, and 65-fold induction in IL-6, IL-1b, and TNFa, respectively, whereas LPS administration led to ;15-, 210-, and 160-fold inductions (Ghose et al, 2008(Ghose et al, , 2009). The differential regulation of DME/transporter genes by LTA and LPS may be caused by the differences in induction levels of the cytokines.…”

“…TLRs are present on nonparenchymal cells, including Kupffer cells, as well as on hepatocytes in the liver (Liu et al, 2002;Matsumura et al, 2003). We have shown that activation of TLR4 by lipopolysaccharide (LPS) (Gram-negative bacterial component) downregulates the gene expression of select DMEs and transporters (Ghose et al, 2008). LPS-treated rodents are well-established models of inflammation, and LPS treatment induces proinflammatory cytokines, interleukin (IL)-6, IL-1b, and tumor necrosis factor (TNF)a.…”

Differential Role of Toll-Interleukin 1 Receptor Domain-Containing Adaptor Protein in Toll-Like Receptor 2-Mediated Regulation of Gene Expression of Hepatic Cytokines and Drug-Metabolizing Enzymes

“…Because of the unique anatomical link between the liver and intestines, Kupffer cells encounter high levels of gut-derived toxins (Su, 2002;Seki and Brenner, 2008). We have previously shown that TIRAP was also not involved in TLR4-mediated induction of hepatic cytokines (Ghose et al, 2008). These results indicate that Kupffer cells may not require TIRAP to recruit MyD88 to initiate signaling, whereas hepatocytes may require TIRAP to recruit MyD88.…”