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Changes in gene expression induced by aromatic amine drugs: testing the danger hypothesis
1Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Ontario, Canada.
Journal of Immunotoxicology
|September 14, 2012
Summary
Primary aromatic amines in drugs can cause dangerous immune reactions. This study found that while some drugs induced cell stress signals in rats, others did not, suggesting new biomarkers for predicting drug reaction risk.
Area of Science:
- Pharmacology
- Toxicology
- Immunology
Background:
- Primary aromatic amines in drugs are linked to high rates of idiosyncratic drug reactions (IDRs).
- The Danger Hypothesis suggests that cell stress signals, induced by reactive metabolites of aromatic amines, may initiate immune responses and serve as IDR risk biomarkers.
- Previous studies in mice showed sulfamethoxazole (SMX) did not increase cell stress genes, unlike other aromatic amines.
Purpose of the Study:
- To determine if the lack of cell stress gene induction by SMX observed in mice is species-specific.
- To identify potential biomarkers of IDR risk common to aromatic amines in rats.
- To investigate the hepatic gene expression changes induced by SMX, dapsone (DDS), and aminoglutethimide (AMG) in rats.
Main Methods:
- Rats were treated with SMX, DDS, and AMG.
- Hepatic gene expression was analyzed using microarrays.
- Changes in specific gene pathways, including the Keap-1-Nrf2-ARE pathway, were examined.
Main Results:
- SMX induced minimal gene changes in rat liver, with no indication of cell stress.
- DDS and AMG treatment led to the upregulation of enzymes like aldo-keto reductase, glutathione-S-transferase, and aldehyde dehydrogenase, potentially indicating danger signals.
- Early insulin-induced hepatic gene (Eiih) was upregulated by all three drugs, while Keap-1-Nrf2-ARE pathway changes varied significantly between drugs.
Conclusions:
- The minimal liver gene changes observed in rats, despite the high incidence of IDRs associated with aromatic amines, suggest that bioactivation by immune cells, rather than liver-specific stress, may be key to IDR initiation.
- Enzymes such as aldo-keto reductase, glutathione-S-transferase, and aldehyde dehydrogenase, along with Eiih, may serve as potential danger signals and biomarkers for predicting IDR risk.
- Findings support the need for further investigation into immune cell-mediated mechanisms underlying aromatic amine-induced IDRs.
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