Investigation of the Mechanisms of Aromatic Amine-induced Idiosyncratic Drug Reactions

Drugs with the primary aromatic amine structure are notorious structural alerts in drug development because of their association with a high incidence of idiosyncratic drug reactions (IDRs). The toxicity of aromatic amines has been attributed to the formation of reactive metabolites common to this functional group that can form antigenic substances and redox cycle to induce oxidative stress. To date, there has not been a systematic study to investigate the mechanisms of aromatic amine-induced IDRs. Therefore, in the first part of my thesis, the danger hypothesis was tested through a global screen of hepatic gene expression in rats treated acutely with the aromatic amine drugs sulfamethoxazole (SMX), dapsone (DDS), and aminoglutethimide (AMG). Although one gene, Eiih, was up-regulated by all drugs tested and could be a general biomarker to drugs that induce IDRs, few changes were found that are likely to represent danger signals. To confirm this, a more comprehensive study was performed on the liver with AMG after longer treatment intervals. Despite substantial changes in apoptotic and mitochondrial pathways, there were few immune changes and no histological evidence of damage. These findings suggest that the liver is not a direct target of aromatic amine drugs or, if it is, the default response may be immune tolerance. The presence of myeloperoxidase in neutrophils and antigen presenting cells provides a more plausible mechanism of aromatic amine toxicity through direct activation of the immune system, and this was tested in the second part of my thesis research. A significant increase in activated neutrophils was observed in AMG-treated rats, which was attributed to an increase in granulocyte progenitors in the bone marrow. This effect is opposite to the agranulocytosis that is observed with AMG clinically, but it may have important implications to the early effects preceding the pathology. In the spleen and lymph nodes, T-cell proliferation was found with simultaneous indications of immune modulation through differential intracellular cytokine expression. Moreover, down-regulation of immune activation may be why the AMG-treated rats do not develop hypersensitivity. Further investigations into tolerogenic mechanisms may have broader implications into why IDRs only develop in a subset of patients.Ph