RT Journal Article
SR Electronic
T1 DOWN-REGULATION OF MOUSE ORGANIC ANION-TRANSPORTING POLYPEPTIDE 4 (Oatp4; Oatp1b2; Slc21a10) mRNA BY LIPOPOLYSACCHARIDE THROUGH THE TOLL-LIKE RECEPTOR 4 (TLR4)
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1265
OP 1271
DO 10.1124/dmd.32.11.1265
VO 32
IS 11
A1 Ning Li
A1 Supratim Choudhuri
A1 Nathan J. Cherrington
A1 Curtis D. Klaassen
YR 2004
UL http://dmd.aspetjournals.org/content/32/11/1265.abstract
AB Lipopolysaccharide (LPS) causes a systemic reaction known as sepsis, which is frequently associated with cholestasis. Many biological effects produced by LPS are thought to be mediated by Toll-like receptor 4 (TLR4). Organic anion-transporting polypeptide 4 (Oatp4; Slc21a10) mediates hepatic uptake of bile acids and other organic anions. The purpose of this study was to determine 1) whether LPS decreases Oatp4 mRNA levels; 2) the role of TLR4 in the LPS-induced down-regulation of Oatp4; and 3) the time course of serum concentrations of tumor necrosis factor α, interleukin (IL) 1β, and IL-6 after LPS administration. For the dose-response study, LPS (1 mg/kg i.p.) produced a significant decrease in Oatp4 mRNA levels in TLR4-normal C3H/OuJ mice, and higher doses produced slightly greater decreases. However, none of the doses of LPS examined significantly decreased Oatp4 mRNA levels in TLR4-mutant C3H/HeJ mice. For the time-response study, LPS (5 mg/kg i.p.) produced a rapid decrease in Oatp4 mRNA levels in TLR4-normal C3H/OuJ mice. The maximal decrease in Oatp4 mRNA levels (80%) was observed 12 h after LPS administration and returned to control levels thereafter. In contrast, LPS did not produce a significant decrease in Oatp4 mRNA levels at any time in TLR4-mutant C3H/HeJ mice. These findings demonstrate that LPS decreases Oatp4 mRNA levels in mice, and the decrease is mediated through TLR4. The American Society for Pharmacology and Experimental Therapeutics