title: Bacterial lipopolysaccharide enhances aflatoxin B1 hepatotoxicity in rats by a mechanism that depends on tumor necrosis factor alpha.
abstract: Exposure to a nontoxic dose of bacterial endotoxin (lipopolysaccharide [LPS]) potentiates the hepatotoxicity of aflatoxin B(1) (AFB(1)). Because some of the pathophysiologic effects associated with LPS are mediated through tumor necrosis factor alpha (TNF-alpha), this study was conducted to explore the role of TNF-alpha in the AFB(1)/LPS model. Male Sprague-Dawley rats (250-300 g) were treated with either 1 mg AFB(1)/kg, intraperitoneally, or its vehicle (0.5% dimethyl sulfoxide [DMSO]/water), and 4 hours later with either Escherichia coli lipopolysaccharide (7.4 x 10(6)EU/kg, intravenously) or its saline vehicle. LPS administration resulted in a marked rise in TNF-alpha levels at 6 hours, which preceded the onset of liver injury. TNF-alpha messenger RNA (mRNA) in liver was increased by LPS treatment. The mRNA of receptors (R1 and R2) for TNF-alpha was also examined. R1 mRNA levels were not altered; however, R2 mRNA levels were increased by either AFB(1) or LPS administration. To determine if TNF-alpha plays a causal role in the development of liver injury, the increase in TNF-alpha was attenuated by administration of either pentoxifylline or anti-TNF-alpha serum, and liver injury was assessed. Administration of either of these agents resulted in protection. LPS treatment resulted in the upregulation of gene transcription for cyclooxygenase-2 (COX-2). However, administration of the selective COX-2 inhibitor NS-398 did not decrease injury. TNF-alpha and COX-2 inhibitors did not affect hepatic sequestration of neutrophils. Furthermore, it did not appear that TNF-alpha contributed to injury through inhibition of tissue repair. These data support the hypothesis that LPS-induced expression of TNF-alpha underlies the potentiation of AFB(1)-induced hepatotoxicity.
authors: Department of Pharmacology and Toxicology, National Food Safety & Toxicology Center and Institute for Environmental Toxicology, Michigan State University, East Lansing, MI 48824, USA.
authors: C C
authors: CC
authors: Barton
authors: E X
authors: EX
authors: Barton
authors: P E
authors: PE
authors: Ganey
authors: S L
authors: SL
authors: Kunkel
authors: R A
authors: RA
authors: Roth
mesh_terms: D016604:Aflatoxin B1 / Q000506:poisoning*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001659:Biliary Tract / Q000187:drug effects / Q000473:pathology; D051546:Cyclooxygenase 2; D004357:Drug Synergism; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D008115:Liver Regeneration / Q000502:physiology; D008297:Male; D009504:Neutrophils / Q000473:pathology; D010431:Pentoxifylline / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000502:physiology*
chemical_list: D000906:Antibodies; D007527:Isoenzymes; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D016604:Aflatoxin B1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D010431:Pentoxifylline