Endotoxin pretreatment protects against the hepatotoxicity of acetaminophen and carbon tetrachloride: role of cytochrome P450 suppression

• Published in: Toxicology (Amsterdam) 2000-07, Vol.147 (3), p.167-176
• Main Authors: Liu, Jie, Sendelbach, Louis E, Parkinson, Andrew, Klaassen, Curtis D
• Format: Article
• Language: English
• Subjects: Acetaminophen - toxicity; Alanine Transaminase - blood; Analgesics, Non-Narcotic - toxicity; Animals; Biological and medical sciences; Carbon Tetrachloride - toxicity; Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System - physiology; Cytochrome P450; Digestive system; Endotoxin tolerance; Hepatoprotection; Interleukin-1 - therapeutic use; Interleukin-1α; Lipopolysaccharides - therapeutic use; Liver - drug effects; Liver - enzymology; Liver Diseases - enzymology; Liver Diseases - prevention & control; Male; Medical sciences; Mice; Mice, Inbred C3H; Pharmacology. Drug treatments; Strain difference
• ISSN: 0300-483X; 1879-3185
• DOI: 10.1016/S0300-483X(00)00193-1

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 6β-, 2β-, and 15β-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-1α, 5×10 5 U/mouse), and the hepatoprotection and hepatic P450 enzymes were examined. IL-1α 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-1α, which in turn suppresses the cytochrome P450 responsible for the activation of acetaminophen and CCl 4 to reactive metabolites.