Is exposure to bacterial endotoxin a determinant of susceptibility to intoxication from xenobiotic agents?
Why certain individuals are more susceptible than others to harmful effects of chemical exposure remains incompletely understood. One understudied but potentially important determinant of susceptibility is concurrent or preexisting inflammation that may influence the pathogenic outcome of chemical exposure. Endotoxin from gram-negative bacteria is a potent inducer of inflammation. We are all exposed to endotoxin, and such exposure varies considerably among individuals depending on environment, bacterial infection, and conditions that affect its translocation from the lumen of the gastrointestinal tract into the circulation. Mammals have a vigorous response to endotoxin that includes recruitment and activation of inflammatory cells and release of many soluble mediators that affect cellular homeostasis. These and other results have led to the hypothesis that altered tissue homeostasis initiated by small, otherwise nontoxic doses of xenobiotic agents can progress to overt toxicity in the presence of inflammatory factors generated by concurrent endotoxin exposure. This hypothesis is supported by studies in animals, in which considerable evidence has accumulated indicating that endotoxin exposure can influence the magnitude of responses to toxic chemicals. For example, exposure to small amounts of endotoxin markedly augments liver injury from a variety of hepatotoxicants including carbon tetrachloride, ethanol, cadmium, halothane, allyl alcohol, and others. Although support for this hypothesis exists, much remains to be learned about the mechanisms by which endotoxin augments chemical toxicity and the implications for human health. Given the ubiquitous and variable exposure of people and animals to endotoxin, this inducer of inflammation should receive serious consideration as a potential determinant of susceptibility to toxic chemicals.
Roth
R A
RA
Department of Pharmacology and Toxicology, Michigan State University, East Lansing 48824, USA. rothr@pilot.msu.edu
Harkema
J R
JR
Pestka
J P
JP
Ganey
P E
PE
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D004064:Digestive System / Q000378:metabolism; D004198:Disease Susceptibility; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004781:Environmental Exposure; D006801:Humans; D008070:Lipopolysaccharides / Q000009:adverse effects* / Q000378:metabolism; D008107:Liver Diseases / Q000473:pathology; D015262:Xenobiotics / Q000009:adverse effects* / Q000633:toxicity
D008070:Lipopolysaccharides; D015262:Xenobiotics