RT Journal Article
SR Electronic
T1 ENDOTOXIN-MEDIATED DISTURBANCE OF HEPATIC CYTOCHROME P450 FUNCTION AND DEVELOPMENT OF ENDOTOXIN TOLERANCE IN THE RAT MODEL OF DEXTRAN SULFATE SODIUM-INDUCED EXPERIMENTAL COLITIS
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 437
OP 441
DO 10.1124/dmd.32.4.437
VO 32
IS 4
A1 Masubuchi, Yasuhiro
A1 Horie, Toshiharu
YR 2004
UL http://dmd.aspetjournals.org/content/32/4/437.abstract
AB Hepatobiliary abnormalities have been described in patients with chronic inflammatory bowel diseases. Hepatic cytochrome P450 (P450)-dependent drug-metabolizing enzyme activities and susceptibility to a hepatotoxin, d-galactosamine, were determined in rats with dextran sulfate sodium (DSS)-induced colitis to assess whether liver function is affected in the model of inflammatory bowel disease. Colitis was induced by treatment of rats with 3% DSS in drinking water for 7 days. Liver microsomes for enzyme activities and serum for biological analysis were prepared from the rats with colitis, along with untreated and lipopolysaccharide (LPS)-treated rats. Other rats received intraperitoneal injection of d-galactosamine to assess their susceptibility to the toxin-induced liver injury. Treatment of rats with DSS resulted in not only colitis but also decreases in hepatic P450-dependent drug-metabolizing enzyme activities. Elevated endotoxin was found in portal blood, which was not associated with liver injury. The potency and the isoform selectivity in the suppression of the P450 enzymes by DSS treatment were similar to those of LPS-treated rats. Coadministration of antibiotics, polymyxin B or metronidazole, with DSS protected rats from decreases in some but not all P450 enzyme activities, indicating partial involvement of bacterial endotoxin in the P450 decreases. The rats with colitis were less susceptible than untreated rats to d-galactosamine-induced liver injury and TNF-α production, suggesting development of endotoxin tolerance in DSS-colitis. In conclusion, these results suggest that the DSS-colitis leads to endotoxin-mediated down-regulation of hepatic P450 enzymes and protection against d-galactosamine-induced liver injury, probably due to endotoxin tolerance. The American Society for Pharmacology and Experimental Therapeutics