Variability of the Genes Involved in the Cellular Redox Status and Their Implication in Drug Hypersensitivity Reactions

Abstract

Adverse drug reactions are a major cause of morbidity and mortality. Of the great diversity of drugs involved in hypersensitivity drug reactions, the most frequent are non-steroidal anti-inflammatory drugs followed by β-lactam antibiotics. The redox status regulates the level of reactive oxygen and nitrogen species (RONS). RONS interplay and modulate the action of diverse biomolecules, such as inflammatory mediators and drugs. In this review, we address the role of the redox status in the initiation, as well as in the resolution of inflammatory processes involved in drug hypersensitivity reactions. We summarize the association findings between drug hypersensitivity reactions and variants in the genes that encode the enzymes related to the redox system such as enzymes related to glutathione: Glutathione S-transferase (GSTM1, GSTP, GSTT1) and glutathione peroxidase (GPX1), thioredoxin reductase (TXNRD1 and TXNRD2), superoxide dismutase (SOD1, SOD2, and SOD3), catalase (CAT), aldo-keto reductase (AKR), and the peroxiredoxin system (PRDX1, PRDX2, PRDX3, PRDX4, PRDX5, PRDX6). Based on current evidence, the most relevant candidate redox genes related to hypersensitivity drug reactions are GSTM1, TXNRD1, SOD1, and SOD2. Increasing the understanding of pharmacogenetics in drug hypersensitivity reactions will contribute to the development of early diagnostic or prognosis tools, and will help to diminish the occurrence and/or the severity of these reactions.

Keywords: hypersensitivity drug reaction; non-steroidal anti-inflammatory drugs; redox; β-lactam antibiotics and SNPs.

Figure 1

Potential role of redox regulation in the development of drug hypersensitivity reactions. The mitochondrial electron transport chain (ETC) produces superoxide (O₂^•−) that is converted into hydrogen peroxide (H₂O₂) by means of SOD2. Acetaminophen (APAP) and indomethacin (INDO) may cause mitochondrial dysfunction and alter the redox status through the inactivation of mitochondrial ETC components. The H₂O₂ can cross the membrane and be converted into hydroxyl radical and water by catalase. Cytosolic, polyunsaturated fatty acids (PUFA) are susceptible to oxidation and lead to the generation of reactive aldehydes (RHs) and isoprostanes. Also, the O₂^•− generated by ETC can cross the mitochondrial membrane and be converted into peroxynitrite (ONOO⁻) spontaneously in the presence of nitric oxide (NO). The ONOO⁻ generated can up-regulate COX activity resulting in an increase in the production of prostanoids. Besides, the enzyme AKR1B1 may regulate PGE2 production through PGF2α reduction. The plasma membrane protein NADPH-oxidase (NOX) can generate O₂^•− that is transformed into H₂O₂ by the extracellular SOD3. Finally, H₂O₂ can cross the membrane via aquaporins (AQP) or participate as a second messenger and activate effector molecules via the action of PRDX and TXNRD. These extracellular enzymes can modulate several pathophysiological processes, such as immune response and inflammation. In the cytosol, AMPK protein kinase can be activated by ROS and inhibit inflammation. The redox status can activate signal transduction cascades and induce changes in transcription factors that modulate the expression of inflammatory mediators. Drug biotransformation (either bioactivation or detoxication) may generate reactive metabolites. The most common detoxication process is carried out through conjugation with GSH. These metabolites have the potential to act as haptens and play as antigenic determinants to trigger the adaptive immune response. Moreover, the danger hypothesis proposes the necessary activation of the immune system by stressed cells, which is mediated by certain molecules that act as danger signals. Thus, molecules involved in oxidative stress response can act as potential danger signals. Besides ROS originated at the mitochondria, these species are also produced in response to cytokines and growth factor receptors. Enzymes such as CAT, PRDX, GPXs, SOD, GSTs, and GSH can reduce the cytoplasmic ROS levels. The redox status can activate signal transduction cascades and induce changes in redox-dependent transcription factors, such as NF-κB which leads to the subsequent expression of cytokines and interleukins IL-1, IL-6, and IL-8. Also, the cytokines secretion is regulated by several signaling pathways involving the JAK-STAT pathways, and the STAT transcription factor family requires ROS species for their transcriptional activity. Nrf2 is involved in the inflammatory response which protects against airway inflammation and asthma. In the nucleus, DNA damage and repair processes are a source of ROS. These redox-dependent transcription factors have cysteine residues which are also regulated by the redox status of the nucleus.