MECHANISMS OF DRUG-INDUCED TOXICITIES

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It is generally believed that drug-induced allergic hepatitis, a rare but life-threatening adverse drug reaction, is caused by an immune reaction against liver tissue that has been irreversibly altered by a reactive metabolite of a drug. This year we have investigated those factors that may determine the susceptibility of an individual to develop this type of adverse drug reaction. In one study, we investigated the role of oral tolerance, an antigen-specific immunological hyporesponsiveness induced by the oral administration of antigens, in preventing drug-induced allergic hepatitis. Although recent evidence suggests that the liver may have a role in the induction of oral tolerance against protein antigens, relatively little work has been done to explore the role of the liver in tolerance caused by the oral administration of drugs and other sensitizing chemicals. As an initial step to address this problem, we fed the skin-sensitizing agent 2,4-dinitrochlorobenzene (DNCB) to mice prior to sensitizing and challenging them with this compound. In another set of animals, DNCB was fed to mice and protein adducts of DNCB were measured in the liver immunohistochemically and by immunoblotting with the use of polyclonal antibodies raised against the dinitrophenyl (DNP) hapten. It was found that the feeding of DNCB to mice inhibited the ear swelling effects of DNCB and led to the formation of protein adducts of DNCB in hepatocytes and Kupffer cells of the liver. Since these cells have been suggested to have a role in the induction of oral tolerance against protein antigens, they may also inhibit immune reactions against protein adducts of drugs that are formed in the liver after a drug has been administered orally. In this regard, it was found in other studies that anti-inflammatory cytokines and other factors, such as interleukins 4,10, 11, and 13, and cortisol, were rapidly secreted into the blood, when metabolites of halothane and acetaminophen formed protein adducts in the liver. It is believed that these factors may have a protective role by preventing subsequent cell mediated immune reactions against liver proteins that have been modified by reactive metabolites of drugs. Perhaps individuals who develop drug-induced allergic hepatitis have a defect in the regulation of one or more of these anti-inflammatory factors.