RGD Reference Report - Bacterial lipopolysaccharide enhances aflatoxin B1 hepatotoxicity in rats by a mechanism that depends on tumor necrosis factor alpha. - Rat Genome Database

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Bacterial lipopolysaccharide enhances aflatoxin B1 hepatotoxicity in rats by a mechanism that depends on tumor necrosis factor alpha.

Authors: Barton, C C  Barton, E X  Ganey, P E  Kunkel, S L  Roth, R A 
Citation: Barton CC, etal., Hepatology. 2001 Jan;33(1):66-73. doi: 10.1053/jhep.2001.20643.
RGD ID: 14696804
Pubmed: PMID:11124822   (View Abstract at PubMed)
DOI: DOI:10.1053/jhep.2001.20643   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Chemical and Drug Induced Liver Injury  ISOTnf (Rattus norvegicus)14696804; 14696804protein:increased expression:serum (rat)RGD 
Chemical and Drug Induced Liver Injury  IEP 14696804protein:increased expression:serum (rat)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Tnf  (tumor necrosis factor)

Genes (Mus musculus)
Tnf  (tumor necrosis factor)

Genes (Homo sapiens)
TNF  (tumor necrosis factor)


Additional Information