GSTP1-1 is a key factor for cellular adaptation to oxidative stress at multiple levels. GSTP1-1 expression is strongly induced by oxidative stress as a defense mechanism through the binding of transcription factors, like Nrf-2 and activator protein (AP)-1, to the antioxidant response elements in its promoter (Kawamoto et al., 2000; Hayes et al., 2005). In turn, oxidative stress can reversibly inactivate GSTP1-1 by intramolecular disulfide formation or oligomerization (Shen et al., 1993; Sánchez-Gómez et al., 2010). Moreover, several electrophilic agents, including endogenous reactive mediators and drugs, induce an irreversible crosslinking of the enzyme (Sánchez-Gómez et al., 2013). The main residues involved in these modifications are the most reactive cysteines in GSTP1-1, namely, Cys47, and/or Cys101. Both, GSTP1-1 oligomerization and crosslinking affect its interactions with signaling proteins and stress cascades, as mentioned above.

GSTP1-1 can promote the reversible incorporation of GSH (S-glutathionylation) into low pKa cysteine residues of proteins. This modification modulates protein function, but also protects cysteine residues from further irreversible oxidations (Tew, 2007; Townsend et al., 2009), allowing the reduced form to be regenerated. Proteins S-glutathionylated by GSTP1-1 include Prdx6 (Manevich and Fisher, 2005), AKR1B1, and GSTP1-1 itself (Townsend et al., 2009; Wetzelberger et al., 2010).

Altogether, this evidence illustrates the complex redox regulation of GSTP1-1. Under mild oxidative stress, induction of GSTP1-1 expression and its redox “recycling” function afford cellular protection. However, pharmacological treatments or acute inflammation can inactivate GSTP1-1 either by direct oxidation and/or chemical inhibition. In both cases, allelic variants of GSTP1-1, namely, wild type GSTP1-1 (Ile105, Ala114) and variants: GSTP1-1(Ile105Val, Ala114), GSTP1-1(Ile105Val, Ala114Val), and GSTP1-1(Ile105, Ala114Val), differentially exert protective functions on protein activity and lipid peroxidation, which may influence susceptibility to oxidative stress of subjects carrying the various forms (Manevich et al., 2013).

GSTP1-1 displays multiple interactions with drugs, either catalyzing their detoxification by GSH conjugation or being inactivated by them. These interactions are crucial for cancer therapy. GSTP1-1 overexpression is an important factor involved in tumor chemoresistance (Díez-Dacal and Pérez-Sala, 2012), and therefore, an important drug target, for which structurally diverse inhibitors, including ethacrynic acid, glutathione analogs, GSTP1-1 activatable drugs, and natural compounds have been considered (Singh, 2015). The mechanism of action of these compounds frequently involves binding to cysteine residues and/or GSTP1-1 oligomerization, as it occurs with electrophilic prostaglandins (PGs) or chlorambucil (Sánchez-Gómez et al., 2013). Interestingly, the pattern of GSTP1-1 crosslinking and/or chemical modifications depends on the presence of both substrates and inhibitors, for which this enzyme can be considered a converging platform for the effects of drugs and danger signals arising from oxidative stress or inflammation (Sánchez-Gómez et al., 2013).

GSTP1-1 also keeps important direct or indirect interactions with the mechanism of action of drugs such as acetaminophen (McGarry et al., 2015), acetylsalycilic acid (Baranczyk-Kuzma and Sawicki, 1997), and other non-steroidal anti-inflammatory drugs (Orhan and Sahin, 2001). In fact, GSTP1-1 deficiency correlates with higher acetaminophen toxicity in mice (McGarry et al., 2015). Also, a “ligandin” role of GSTP1-1 should be taken into account, since this abundant cytosolic enzyme can sequester drugs, thus reducing their effective concentrations (Oakley et al., 1999; Lu and Atkins, 2004).

GSTP1-1 also displays multiple interactions with inflammation: it is induced by proinflammatory stimuli, but this could exert a negative feedback on the inflammatory response. GSTP1-1 ameliorates the inflammatory response in several experimental models of tissue damage or inflammation (Xue et al., 2005; Luo et al., 2009). Interestingly, several GST, including GSTP1-1, attenuate the action of the inflammatory mediator 15-deoxy-Δ^{12, 14}-PGJ₂ (15d-PGJ₂; Paumi et al., 2004). Evidence from our laboratory indicates that overexpression of GSTP1-1 in rat mesangial cells reduces the capacity of 15d-PGJ₂ to activate Peroxisome proliferator activated receptor (PPAR) transcription factor(s) (Figure 1). Moreover, a reduction in the basal PPAR activity is also observed, suggesting the inactivation of endogenous PPAR agonists or the participation of additional mechanisms in GSTP1-1 regulation of inflammation.

In turn, electrophilic mediators like 15d-PGJ₂ can inhibit GST activity in several cell types through various mechanisms (Sánchez-Gómez et al., 2007). Interestingly, cyclopentenone prostaglandins (cyPG) with dienone structure induce an extensive intermolecular crosslinking of GSTP1-1 monomers, involving mainly Cys47 and Cys101 (Sánchez-Gómez et al., 2013) that is blocked by GSH or non-metabolizable GSH analogs, indicating that cyPG-GSTP1-1 interaction is impaired in the GSH-bound enzyme.

Therefore, the interaction of GSTP1-1 with inflammatory mediators like cyPG is a two-way process strongly dependent on GSH availability (Gayarre et al., 2005; Díez-Dacal and Pérez-Sala, 2010), since the enzyme can conjugate electrophilic mediators with GSH, whereas cyPG can induce the expression and/or inhibit GST activity in a cell type-dependent manner (Sánchez-Gómez et al., 2007). Some of these interactions have also been evidenced for other GST isoforms (Gilot et al., 2002; Kudoh et al., 2014). These observations illustrate the intricate implications of GST in inflammation, with the net outcome depending on the delicate balance of all these factors.

Although GST have been mostly studied in the fields of oxidative stress and chemoresistance, an interesting role in allergic reactions is emerging. Endogenous GSTP1-1 is an important target for haptenation, which has been related to the induction of certain drug hypersensitivity reactions (Meng et al., 2014). In addition, genetic variants of several GST isoforms have been found to associate with allergic processes including asthma (Tamer et al., 2004), drug eruptions (Ates et al., 2004), sensitization to thimerosal (Westphal et al., 2000), or allergic rhinitis (Iorio et al., 2014). In the case of GSTP1-1, both down- and up-regulations of GSTP1-1 levels have been reported in association with asthma (Schroer et al., 2011): whereas low levels could contribute to asthma, oxidative stress associated with the allergic response could induce GSTP1-1 expression. These changes in expression may in turn be modulated by the occurrence of polymorphisms, like Ile105Val (rs 1695; Dragovic et al., 2014), since this variant has been reported to display a reduced ability to conjugate several electrophilic drugs and reactive metabolites to GSH, and may associate with certain allergic diseases, including atopy and asthma (Hoskins et al., 2013). Polymorphic forms of GSTP1-1 correlate with the aggravation of asthma symptoms induced by air pollution (Su et al., 2013), and increased risk of asthma associated with acetaminophen (Kang et al., 2013) and exercise (Islam et al., 2009). In addition, the Ile105 wild type enzyme associates with enhancement of certain nasal allergic responses (Gilliland et al., 2004), whereas, according to another study, the Ala114 wild type enzyme associates with increased risk of atopy (Schultz et al., 2010). Nevertheless, lack of association of GSTP1-1 polymorphisms with allergic diseases or drug hypersensitivity has been reported in other studies, potentially due to differences in the genetic backgrounds of the patient cohorts studied.

Altogether, these findings support the role of GSTP1-1 as a risk factor in hypersensitivity responses by multiple mechanisms, given its multifunctional involvement in drug metabolism and inflammation. Moreover, GSTP1-1 emerges as a key factor to be considered in future genomic studies related with allergy development and drug hypersensitivity reactions.

AKR1B1 activity is regulated by oxidative posttranslational modifications. The highly nucleophilic Cys298, located near the active site, can be modified by different reactive species like nitric oxide (NO), HNE, or oxidized glutathione. These modifications may reduce or increase AKR1B1 catalytic activity, depending on the modifying moiety, and reduce its susceptibility to pharmacological inhibitors. Interestingly, NADPH protects Cys298 from modification by these agents (Chandra et al., 1997; Del Corso et al., 1998; Petrash, 2004).

AKR1B1 is a target gene of Nrf-2, the master transcription factor regulating the antioxidant response. Therefore, it is induced by numerous oxidative stimuli and participates in the antioxidant response (Kang et al., 2007; Wang et al., 2012). In consequence, AKR1B1 expression is increased in tissues with elevated oxidative stress, e.g., in alcoholic liver disease or vascular inflammation (Srivastava et al., 2005), where in some cases affords a protective role (Kang et al., 2014). Nevertheless, excessive AKR1B1 activity can lead to NADPH depletion and oxidative stress.

This occurs in diabetes, where AKR1B1 metabolizes excess glucose through the polyol pathway. An increased flux through this pathway can lead to osmotic stress due to the increased formation of sorbitol, as well as to a redox imbalance by the elevated consumption of NADPH (Petrash, 2004; Figure 2). NADPH is a substrate/cofactor for several enzymes involved in the cellular antioxidant defense, including glutathione reductase (GSH regeneration), peroxiredoxins and thioredoxin, as well as for several detoxifying systems (Pollak et al., 2007a). Therefore, depletion of NADPH changes the NADPH/NADP⁺ ratio contributing to oxidative stress and reducing the cellular ability to recover after an oxidative insult (Pollak et al., 2007b; Ying, 2008).

AKR1B1 is an important drug target due to its implication in the development of diabetic complications. Therefore, the search for inhibitors from both synthetic and natural sources has yielded a wide array of compounds that bind and/or inhibit the enzyme, with structural information on their binding arising from molecular modeling or crystallographic studies. AKR enzymes are involved in chemoresistance because they metabolize carbonyl-containing drugs, including naloxone and ketotifen (Endo et al., 2014). The anthracycline antibiotics doxorubicin and daunorubicin pose an important case, since they are among the most effective chemotherapic drugs. However, the reduction of their carbonyl group to their corresponding alcohol, yielding doxorubicinol and daunorubicinol, respectively, reduces their efficacy (Veitch et al., 2009). Overexpression of AKR1B1 inactivates these drugs and leads to resistance of various tumor cells (Plebuch et al., 2007; Heibein et al., 2012). Conversely, AKR1B1 inhibition increases the cytotoxic effects of the anticancer agents doxorubicin and cisplatin in HeLa cervical carcinoma cells (Lee et al., 2002), and the AKR inhibitors PGA₁ and AD-5467 improve the effectiveness of doxorubicin in lung cancer cells (Díez-Dacal et al., 2011; Díez-Dacal and Pérez-Sala, 2012). Natural variants of certain AKR enzymes have been identified that present a reduced capacity to metabolize daunorubicin and doxorubicin in vitro (Bains et al., 2008, 2010). There is little information on the involvement of AKR1B1 metabolites in hypersensitivity reactions. Nevertheless, daunorubicinol has toxic effects per se because it induces cardiomyopathy (Minotti et al., 2004).

AKR1B1 plays an important role in different inflammatory diseases such as atherosclerosis, sepsis, asthma, uveitis, and colon cancer. AKR1B1 can be induced by proinflammatory stimuli (Bresson et al., 2012). Transcription factors Nuclear factor (NF)-κB and AP-1 activate the AKR1B1 promoter through binding to the osmotic response element (ORE; Iwata et al., 1997; Lee et al., 2005) and the phorbol ester response or AP-1 sites, respectively (Penning and Drury, 2007).

Although AKR1B1 can play a protective role by detoxifying acrolein or HNE, it can also play a positive/amplifying role in inflammation through various mechanisms (Figure 2). In particular, metabolism of HNE or its glutathione conjugate GS-HNE can result in products, such as 1, 4-dihydroxynonene (DHN) and glutathionyl-1,4-dihydroxynonane (GS-DHN), which are still toxic and promote activation of phospholipase C (PLC)-NF-κB cascades perpetuating inflammation (Ramana et al., 2006; Srivastava et al., 2011). Thus, inhibition of AKR1B1 reduced NF-κB-dependent inflammatory markers, and the synthesis of TNF-α stimulated by hyperglycemic conditions, and of inflammatory mediators like NO and PGE₂ (Ramana and Srivastava, 2010).

Interestingly, AKR1B1 displays PGF2α synthetizing activity through which it can regulate PGE₂ production (Bresson et al., 2012), thus contributing to the modulation of inflammation. In turn, AKR1B1 can bind several PG, including PGE₁ and PGE₂ and their cyclopentenone products, PGA₁ and PGA₂, which results in inhibition of the enzyme (Díez-Dacal et al., 2016). However, whereas binding and inhibition by PGE appear to be fully reversible, cyPG form a Michael adduct that seems irreversible under certain conditions. Nevertheless, concentrations of GSH in the cellular range (millimolar) elicit a retro-Michael reaction, a fact that contributes to explain the more intense modification and inhibition of some AKRs detected in GSH-depleted cells (Díez-Dacal et al., 2011).

Early reports linking AKR1B1 to hypersensitivity provided fragmented pieces of evidence. The AKR1B1 inhibitor sorbinil, not currently used in clinical practice, elicited severe adverse effects, including hypersensitivity attributed to protein adducts produced by sorbinil metabolites (Maggs and Park, 1988). Interestingly, lodoxamide tromethamine, and several anti-allergy drugs, inhibit AKR1B1 (White, 1981), providing additional possibilities of interaction with the hypersensitivity response.

Recent studies using pharmacological or genetic depletion establish a positive role for AKR1B1 in allergy. In mice, AKR1B1 inhibition reduced airway inflammation, hyperresponsiveness and IgE and Th2-cytokine levels in ovalbumin and ragweed pollen extract-induced asthma (Yadav et al., 2009, 2011a). Furthermore, studies in AKR^−/− mice also support a role of AKR1B1 in the pathogenesis of asthma and allergic rhinitis (Yadav et al., 2011b, 2013a). Moreover, the efficacy of AKR1B1 inhibitors in mouse models supports their use to treat these allergic conditions (Yadav et al., 2011b, 2013a). In mice sensitized with ovalbumin, AKR1B1 inhibition with fidarestat prevented the airway remodeling observed in chronic asthma by blocking the tumor growth factor β (TGFβ), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Protein kinase B (PKB/AKT)/Glycogen synthase kinase-3 beta (GSK3B) axis (Yadav et al., 2013b).

The mechanisms linking AKR1B1 with allergy are not fully understood. Nevertheless, it could be hypothesized that it provides coactivators of the allergic response through its contribution to oxidative stress or to the generation of proinflammatory mediators, like aldehyde conjugates.

In contrast to the numerous studies on GSTP1-1 polymorphisms in allergic patients, most genetic studies on AKR1B1 have been directed to explore its association with the development of diabetic implications (Demaine, 2003), and very little information exists on the impact of AKR1B1 variants on drug metabolism or hypersensitivity reactions. Nevertheless, given the fact that an increased glucose flux through the polyol pathway leads to redox imbalance, it would be interesting to assess the involvement of AKR1B1 variants in oxidative stress. In addition, the recent evidences on the involvement of AKR1B1 in allergy grant its study in association with these processes.

In summary, AKR and GST enzymes are emerging as important regulators of the balance of inflammatory mediators. This, together with their association with allergic processes and their ability to metabolize and be covalently modified by drugs makes them attractive candidates to explore their involvement not only in allergy in general but in drug hypersensitivity.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.