Increased Sensitivity of Glutathione<i>S</i>-Transferase P-Null Mice to Cyclophosphamide-Induced Urinary Bladder Toxicity

Conklin, Daniel J.; Haberzettl, Petra; Lesgards, Jean-François; Prough, Russell A.; Srivastava, Sanjay; Bhatnagar, Aruni

doi:10.1124/jpet.109.156513

Cited by 53 publications

(71 citation statements)

References 37 publications

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“…In an initial study of these animals, Henderson et al (1998) reported that the activity toward CDNB was reduced in lung cytosolic fractions but not in the fractions prepared from the kidney and liver. However, a later study reported reduced activity toward CDNB in cytosolic extracts prepared from liver, lung, and kidney of this same mouse line, with the most dramatic reduction observed in the liver (Conklin et al, 2009). A possible explanation for these disparate findings is the different genetic background of the GSTP-deficient mice.…”

Section: Discussionmentioning

confidence: 77%

“…Mice lacking individual GST genes have provided some functional insight into the role of these enzymes in drug metabolism and risk from environmental carcinogens, especially in the case of GSTP (Henderson et al, 2000;Conklin et al, 2009). However, generating a panel of mice lacking each of the 22 cytosolic mouse GSTs to assess their role in development and normal physiology as well as biotransformation of drugs and xenobiotics would be an arduous undertaking.…”

Section: Introductionmentioning

confidence: 99%

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Mice Lacking Three Loci Encoding 14 Glutathione Transferase Genes: A Novel Tool for Assigning Function to the GSTP, GSTM, and GSTT Families

et al. 2014

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Glutathione S-transferases (GSTs) form a superfamily defined by their ability to catalyze the conjugation of glutathione with electrophilic substrates. These enzymes are proposed to play a critical role in protection of cellular components from damage mediated by reactive metabolites. Twenty-two cytosolic GSTs, grouped into seven families, are recognized in mice. This complexity hinders the assignment of function to a subset or family of these genes. We report generation of a mouse line in which the locus encoding three GST gene families is deleted. This includes the four Gstt genes spanning 65 kb on chromosome 10 and the seven Gstm genes found on a 150 kb segment of DNA chromosome 3. In addition, we delete two Gstp genes on chromosome 19 as well as a third related gene located 15 kb telomeric to Gstp1 and Gstp2, which we identify as a potential new member of this gene family. We show that, despite the loss of up to 75% of total GST activity in some tissues from these animals, the mice are healthy and fertile, with normal life expectancy. The normal development and health of these animals make them an appropriate model for defining the role of these families in redox homeostasis and metabolism of drugs and environmental pollutants.

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Section: Discussionmentioning

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Mice Lacking Three Loci Encoding 14 Glutathione Transferase Genes: A Novel Tool for Assigning Function to the GSTP, GSTM, and GSTT Families

et al. 2014

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“…Wolf (University of Dundee) and maintained as independent lines for use in this study (16). Similarly, GRX-TG, GRX-null, and matching WT mice were all backcrossed on a B/6 background, and littermates were used as appropriate controls (17).…”

Section: Methodsmentioning

confidence: 99%

Postischemic Deactivation of Cardiac Aldose Reductase

Wetzelberger

Baba

Thirunavukkarasu

et al. 2010

Journal of Biological Chemistry

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Aldose reductase (AR) is a multifunctional enzyme that catalyzes the reduction of glucose and lipid peroxidation-derived aldehydes. During myocardial ischemia, the activity of AR is increased due to the oxidation of its cysteine residues to sulfenic acids. It is not known, however, whether the activated, sulfenic form of the protein (AR-SOH) is converted back to its reduced, unactivated state (AR-SH). We report here that in perfused mouse hearts activation of AR during 15 min of global ischemia is completely reversed by 30 min of reperfusion. During reperfusion, AR-SOH was converted to a mixed disulfide (AR-SSG). Deactivation of AR and the appearance of AR-SSG during reperfusion were delayed in hearts of mice lacking glutathione S-transferase P (GSTP). In vitro, GSTP accelerated glutathiolation and inactivation of AR-SOH. Reduction of AR-SSG to AR-SH was facilitated by glutaredoxin (GRX). Ischemic activation of AR was increased in GRX-null hearts but was attenuated in the hearts of cardiospecific GRX transgenic mice. Incubation of AR-SSG with GRX led to the regeneration of the reduced form of the enzyme. In ischemic cardiospecific AR transgenic hearts, AR was co-immunoprecipitated with GSTP, whereas in reperfused hearts, the association of AR with GRX was increased. These findings suggest that upon reperfusion of the ischemic heart AR-SOH is converted to AR-SSG via GSTP-assisted glutathiolation. AR-SSG is then reduced by GRX to AR-SH. Sequential catalysis by GSTP and GRX may be a general redox switching mechanism that regulates the reduction of protein sulfenic acids to cysteines.Myocardial ischemia-reperfusion results in the induction of oxidative stress. Ischemia increases the generation of free radicals and reactive oxygen species (ROS), 2 and the generation of these species is increased further upon reperfusion. In several, but not all, models of ischemia-reperfusion injury, redox changes correlate with functional impairment (1-6). The role of free radicals in inducing myocardial injury was supported by early studies showing that treatment with enzymatic and nonenzymatic antioxidants decreased ischemia-reperfusion injury; however, results with exogenous chemicals or enzymatic antioxidants have not been universally positive. In contrast, newer molecular studies with transgenic and gene-deleted animals provide more rigorous and compelling evidence that oxidative stress is a significant component of ischemia-reperfusion injury. Nonetheless, the mechanisms by which ROS induce ischemia-reperfusion injury remain poorly understood.Although in earlier studies it was assumed that an increase in ROS generation is universally detrimental, more recent work shows that in contrast to their injurious effects at high concentrations ROS at low concentrations can stimulate signaling pathways. Some of these signal transduction events stimulate adaptation and increase tissue resistance to oxidative stress. For instance, it has been shown that brief bouts of ischemia that trigger myocardial preconditioning generate oxidative str...

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“…There is no doubt that the major function of GSTs is to conjugate GSH with electrophilic substrates; however, it was also reported that some GST isoforms possibly play a role in the control of the intracellular signaling pathway (Adler et al, 1999;Dorion et al, 2002). For example, cyclophosphamide-induced nephrotoxicity was potentiated in GSTP-null mice compared with wildtype mice (Conklin et al, 2009). A reactive metabolite of cyclophosphamide conjugated with mercapturic acid, which is derived from its GSH conjugates, was excreted in the urine to the same extent in both types of mice, whereas mitogen-activated protein kinase in bladder was more activated in GSTP-null mice than in wild-type mice.…”

Section: Gst Isoformsmentioning

confidence: 99%

Involvement of Different Human Glutathione Transferase Isoforms in the Glutathione Conjugation of Reactive Metabolites of Troglitazone

Okada

Maeda²,

Nishiyama³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Null mutation of glutathione transferase (GST) M1 and GSTT1 was reported to correlate statistically with an abnormal increase in the plasma levels of alanine aminotransferase or aspartate aminotransferase caused by troglitazone in diabetic patients (Clin Pharmacol Ther, 73:435-455, 2003). This clinical evidence leads to the hypothesis that GSH conjugation catalyzed by GSTT1 and GSTM1 has a role in the elimination of reactive metabolites of troglitazone. However, the contribution of GST isoforms expressed in human liver to the detoxification of reactive metabolites of troglitazone has not yet been clarified. We investigated the involvement of human GST isoforms in the GSH conjugation of reactive metabolites of troglitazone using recombinant GST enzymes. Five reported GSH conjugates of reactive metabolites were produced from troglitazone after incubation with liver microsomes, NADPH, and GSH in a GSH concentration-dependent manner. Addition of human recombinant GSTA1, GSTA2, GSTM1, or GSTP1 protein to the incubation mixture further increased the GSH conjugates. However, the addition of GSTT1 did not show any catalytic effect. It is of interest that one of the reactive metabolites with a quinone structure was predominantly conjugated with GSH by GSTM1. Thus, we demonstrated that the GST isoforms contributed differently to the GSH conjugation of individual reactive metabolites of troglitazone, and GSTM1 is the most important GST isoform in the GSH conjugation of a specific reactive metabolite produced from the cytotoxic, quinone-form metabolite of troglitazone.

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Increased Sensitivity of GlutathioneS-Transferase P-Null Mice to Cyclophosphamide-Induced Urinary Bladder Toxicity

Cited by 53 publications

References 37 publications

Mice Lacking Three Loci Encoding 14 Glutathione Transferase Genes: A Novel Tool for Assigning Function to the GSTP, GSTM, and GSTT Families

Mice Lacking Three Loci Encoding 14 Glutathione Transferase Genes: A Novel Tool for Assigning Function to the GSTP, GSTM, and GSTT Families

Postischemic Deactivation of Cardiac Aldose Reductase

Involvement of Different Human Glutathione Transferase Isoforms in the Glutathione Conjugation of Reactive Metabolites of Troglitazone

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