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 to xicity of many hepatotoxicants. However, exposure to a sublethal dose of LP S renders animals tolerant to a lethal dose of LPS, and protects against th e toxicity of some chemicals. This study was designed to examine the effect s of LPS pretreatment on acetaminophen- and carbon tetrachloride (CCl4)-ind uced 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 (CCl4, 30 mg/kg), as indicated by seru m alanine aminotransferase activity. In contrast, pretreatment of C3H/HeJ m ice with 0.1 or 10 mg/kg LPS afforded no protection against the hepatotoxic effects of acetaminophen and CCl4. In an attempt to determine the mechanis m of LPS-induced protection against acetaminophen- and CCl4-induced hepatot oxicity in C3H/OuJ mice, liver cytochrome P450 was determined 24 h after LP S injection. LPS treatment caused a 26% decrease in total P450 content in C 3H/OuJ but not in C3H/HeJ mice. CYP3A-catalized testosterone 6 beta-, 2 bet a-, 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 cytokine s, 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 alph a pretreatment equally protected against the hepatotoxicity of acetaminophe n and CCl4 in both strains, and suppressed the total microsomal P450 and P4 50 enzyme-catalyzed testosterone hydroxylation to a similar extent. In conc lusion, LPS pretreatment suppressed hepatic cytochrome P450 enzymes and pro tected against the hepatotoxicity of acetaminophen and CCl4 in LPS-sensitiv e C3H/OuJ mice, but not in LPS-refractory C3H/HeJ mice. This protective eff ect 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 th e activation of acetaminophen and CCl4 to reactive metabolites. (C) 2000 Pu blished by Elsevier Science Ireland Ltd. All rights reserved.