Endotoxin pretreatment protects against the hepatotoxicity of acetaminophen and carbon tetrachloride: role of cytochrome P450 suppression.
Bacterial endotoxin (lipopolysaccharide, LPS) is known to potentiate the toxicity of many hepatotoxicants. However, exposure to a sublethal dose of LPS renders animals tolerant to a lethal dose of LPS, and protects against the toxicity of some chemicals. This study was designed to examine the effects of LPS pretreatment on acetaminophen- and carbon tetrachloride (CCl(4))-induced liver injury in LPS-sensitive C3H/OuJ and LPS-resistant C3H/HeJ mice. Pretreatment of male C3H/OuJ mice with a single injection of LPS (0. 1 mg/kg, ip, for 24 h) protected against the hepatotoxic effects of acetaminophen (400 mg/kg) and carbon tetrachloride (CCl(4), 30 mg/kg), as indicated by serum alanine aminotransferase activity. In contrast, pretreatment of C3H/HeJ mice with 0.1 or 10 mg/kg LPS afforded no protection against the hepatotoxic effects of acetaminophen and CCl(4). In an attempt to determine the mechanism of LPS-induced protection against acetaminophen- and CCl(4)-induced hepatotoxicity in C3H/OuJ mice, liver cytochrome P450 was determined 24 h after LPS injection. LPS treatment caused a 26% decrease in total P450 content in C3H/OuJ but not in C3H/HeJ mice. CYP3A-catalized testosterone 6 beta-, 2 beta-, and 15 beta-hydroxylation was decreased 40% by LPS only in C3H/OuJ mice. To determine whether the differences to LPS-response in the two stains of mice is mediated by a strain-related difference in the release of cytokines, mice were pretreated with interleukin-1 (IL-1 alpha, 5 x 10(5) U/mouse), and the hepatoprotection and hepatic P450 enzymes were examined. IL-1 alpha pretreatment equally protected against the hepatotoxicity of acetaminophen and CCl(4) in both strains, and suppressed the total microsomal P450 and P450 enzyme-catalyzed testosterone hydroxylation to a similar extent. In conclusion, LPS pretreatment suppressed hepatic cytochrome P450 enzymes and protected against the hepatotoxicity of acetaminophen and CCl(4) in LPS-sensitive C3H/OuJ mice, but not in LPS-refractory C3H/HeJ mice. This protective effect of LPS appears to be mediated through the release of cytokines such as IL-1 alpha, which in turn suppresses the cytochrome P450 responsible for the activation of acetaminophen and CCl(4) to reactive metabolites.
Liu
J
J
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160-7417, USA.
Sendelbach
L E
LE
Parkinson
A
A
Klaassen
C D
CD
D000082:Acetaminophen / Q000633:toxicity*; D000410:Alanine Transaminase / Q000097:blood; D018712:Analgesics, Non-Narcotic / Q000633:toxicity; D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D007375:Interleukin-1 / Q000627:therapeutic use; D008070:Lipopolysaccharides / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008107:Liver Diseases / Q000201:enzymology* / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H
D018712:Analgesics, Non-Narcotic; D065607:Cytochrome P-450 Enzyme Inhibitors; D007375:Interleukin-1; D008070:Lipopolysaccharides; D000082:Acetaminophen; D003577:Cytochrome P-450 Enzyme System; D002251:Carbon Tetrachloride; D000410:Alanine Transaminase