Human cytosolic glutathione-S-transferases: quantitative analysis of expression, comparative analysis of structures and inhibition strategies of isozymes involved in drug resistance

Mohana, Krishnamoorthy; Achary, Anant

doi:10.1080/03602532.2017.1343343

Cited by 28 publications

(45 citation statements)

References 154 publications

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“…These results were in line with data revealing GSTP expression to be significantly upregulated in a variety of drug-resistant solid cancer types (originating from the breast, colon, pancreas, liver, lung, ovary and stomach), and GSTA and GSTM expression to be induced by lower extents in some types of such drug-resistant solid cancers (4,(12)(13)(14)(15)18). However, the protein levels of GSTM2 and GSTA1 were decreased in SGC7901/DDP cells compared with those in parental DDP-susceptible cells.…”

Section: Resultssupporting

confidence: 90%

“…The suppression of GST activity is thus expected to sensitize drug-resistant solid cancer cells to cytotoxic agents (2,(6)(7)(8)(9)(10)(11)(12). However, GSTs play complicated physiological roles in cells, and the expression profiles of GST isozymes in cancer cells have been associated with sex, tissues and organs (4,13,14). The incidence of solid cancers in different origins is associated with various GST isozymes (4).…”

Section: Introductionmentioning

confidence: 99%

“…As a result, siRNAs are promising tools for downregulating the expression of GST isozymes in order to detect their roles in drug resistance (15,16) and to identify GST isozymes that may be suitable targets to sensitize common types of drug-resistant solid cancer to cytotoxic agents. Studies on different cancer cells and tissues have identified the contributions of various GST isozymes to the incidence of drug resistance in common types of solid cancer (4,13,14). However, for drug-resistant cancer cells or tissues, the available studies have been investigating the roles of GST isozyme(s) in one type of drug-resistant solid cancer, and few have been examining the roles of different GST isozymes in different types of drug-resistant solid cancer.…”

Section: Introductionmentioning

confidence: 99%

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Glutathione S‑transferase isozyme alpha 1 is predominantly involved in the cisplatin resistance of common types of solid cancer

Zou

et al. 2018

Oncol Rep

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The roles of glutathione S-transferase pi 1 (GSTP1), glutathione S-transferase mu 2 (GSTM2) and glutathione S-transferase alpha 1 (GSTA1) in cisplatin (DDP)-resistance of solid cancer cells (A549/DDP, SKOV3/DDP and SGC7901/DDP) were compared following expression downregulation with small interfering RNAs (siRNAs). DDP cytotoxicity was reflected by its half maximal inhibition concentration (IC 50 ) calculated from data using a Cell Counting Kit-8 assay; cell apoptosis was examined using flow cytometry and Hoechst 33342 staining. Higher activities of GST were detected in the cytosol of DDP-resistant cells, compared with those in the parental DDP-susceptible cells. The silencing efficacy of each positive siRNA was supported by western blot analysis. GSTP1 silencing resulted in a 4-fold sensitization of SGC7901/DDP cells to DDP cytotoxicity, but negligible sensitization of SKOV3/DDP and A549/DDP cells. GSTM2 silencing sensitized SKOV3/DDP and A549/DDP cells to DDP cytotoxicity by ~2-fold, but did not sensitize SGC7901/DDP cells. Notably, GSTA1 silencing enhanced DDP cytotoxicity in SGC7901/DDP cells by 6-fold, in A549/DDP cells by 5-fold and in SKOV3/DDP cells by 2-fold. The combined actions of positive siRNAs and DDP increased the percentages of apoptotic cells in the DDP-resistant solid cancer cells compared with the combined actions of DDP and the negative siRNAs. The present findings indicated that GSTA1 is a predominant GST isozyme associated with DDP resistance of SGC7901/DDP, A549/DDP and SKOV3/DDP cells; GSTA1-specific inhibitors may be general sensitizers of SGC7901/DDP, A549/DDP and SKOV3/DDP cells to DDP cytotoxicity through the promotion of cell apoptosis.

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Section: Resultssupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Glutathione S‑transferase isozyme alpha 1 is predominantly involved in the cisplatin resistance of common types of solid cancer

Zou

et al. 2018

Oncol Rep

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“…The cytosolic GSTs were the first GSTs to be identified and have been extensively studied (for reviews, see Mannervik and Danielson 1988;Coles et al 1990;Awasthi et al 1994;Hayes and Pulford 1995;Sheehan et al 2001;Hayes et al 2005;Josephy and Mannervik 2006;Wu and Dong 2012;Mohana and Achary 2017;Allocati et al 2018). Later studies showed that GST activity was also present in hepatic microsomal, mitochondrial, peroxisomal, and nuclear fractions (Suga et al 1967;Glatt and Oesch 1977;Kraus and Gross 1979;Morgenstern et al 1979;Wahllander et al 1979;Nishino and Ito 1990b).…”

Section: Introductionmentioning

confidence: 99%

The mercapturic acid pathway

Hanna

Anders

2019

Critical Reviews in Toxicology

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The mercapturic acid pathway is a major route for the biotransformation of xenobiotic and endobiotic electrophilic compounds and their metabolites. Mercapturic acids (N-acetyl-L-cysteine S-conjugates) are formed by the sequential action of the glutathione transferases, c-glutamyltransferases, dipeptidases, and cysteine S-conjugate N-acetyltransferase to yield glutathione S-conjugates, L-cysteinylglycine S-conjugates, L-cysteine S-conjugates, and mercapturic acids; these metabolites constitute a "mercapturomic" profile. Aminoacylases catalyze the hydrolysis of mercapturic acids to form cysteine S-conjugates. Several renal transport systems facilitate the urinary elimination of mercapturic acids; urinary mercapturic acids may serve as biomarkers for exposure to chemicals. Although mercapturic acid formation and elimination is a detoxication reaction, L-cysteine S-conjugates may undergo bioactivation by cysteine Sconjugate b-lyase. Moreover, some L-cysteine S-conjugates, particularly L-cysteinyl-leukotrienes, exert significant pathophysiological effects. Finally, some enzymes of the mercapturic acid pathway are described as the so-called "moonlighting proteins," catalytic proteins that exert multiple biochemical or biophysical functions apart from catalysis.

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“…Glutathione S-transferases, including cytosolic, mitochondrial, and microsomal GSTs, are from a family of enzymes that catalyze the conjugation of a wide variety of electrophilic substrates to GSH (Hayes et al, 2005;Oakley, 2011;Wu and Dong, 2012). Human cytosolic GSTs are one of the major conjugating enzyme systems responsible for the metabolism of xenobiotics (Wu and Dong, 2012;Mohana and Achary, 2017), and they have been assigned into seven classes: GST a, m, p, s, u, v, and z (Mannervik et al, 2005). Substrates for GSTs are electrophilic compounds and include metabolic intermediates such as epoxides, arene oxides, quinones, quinoneimines, sulfoxides, cation radicals, and substrates susceptible to conjugating addition reactions, such as those containing a,b-unsaturated ketones (van Bladeren, 2000;Jancova et al, 2010).…”

Section: Tablementioning

confidence: 99%

Metabolism of Strained Rings: Glutathione S-transferase–Catalyzed Formation of a Glutathione-Conjugated Spiro-azetidine without Prior Bioactivation

Grönberg

Bangur

et al. 2019

Drug Metab Dispos

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AZD1979 [(3-(4-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)phenoxy) azetidin-1-yl)(5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methanone] is a melanin-concentrating hormone receptor 1 antagonist designed for the treatment of obesity. In this study, metabolite profiles of AZD1979 in human hepatocytes revealed a series of glutathionerelated metabolites, including the glutathionyl, cysteinyl, cysteinylglycinyl, and mercapturic acid conjugates. The formation of these metabolites was not inhibited by coincubation with the cytochrome P450 (P450) inhibitor 1-aminobenzotriazole. In efforts to identify the mechanistic features of this pathway, investigations were performed to characterize the structure of the glutathionyl conjugate M12 of AZD1979 and to identify the enzyme system catalyzing its formation. Studies with various human liver subcellular fractions established that the formation of M12 was NAD(P)H-independent and proceeded in cytosol and S9 fractions but not in microsomal or mitochondrial fractions. The formation of M12 was inhibited by ethacrynic acid, an inhibitor of glutathione S-transferases (GSTs). Several human recombinant GSTs, including GSTA1, A2-2, M1a, M2-2, T1-1, and GST from human placenta, were incubated with AZD1979. All GSTs tested catalyzed the formation of M12, with GSTA2-2 being the most efficient. Metabolite M12 was purified from rat liver S9 incubations and its structure elucidated by NMR. These results establish that M12 is the product of the GST-catalyzed glutathione attack on the carbon atom a to the nitrogen atom of the strained spiro-azetidinyl moiety to give, after ring opening, the corresponding amino-thioether conjugate product, a direct conjugation pathway that occurs without the prior substrate bioactivation by P450. SIGNIFICANCE STATEMENT The investigated compound, AZD1979, contains a 6-substituted-2oxa-6-azaspiro[3.3]heptanyl derivative that is an example of strained heterocycles, including spiro-fused ring systems, that are widely used in synthetic organic chemistry. An unusual azetidinyl ringopening reaction involving a nucleophilic attack by glutathione, which does not involve prior cytochrome P450-catalyzed bioactivation of the substrate and which is catalyzed by glutathione transferases, is reported. We propose a mechanism involving the protonated cyclic aminyl intermediate that undergoes nucleophilic attack by glutathione thiolate anion in this reaction, catalyzed by glutathione transferases.

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Human cytosolic glutathione-S-transferases: quantitative analysis of expression, comparative analysis of structures and inhibition strategies of isozymes involved in drug resistance

Cited by 28 publications

References 154 publications

Glutathione S‑transferase isozyme alpha 1 is predominantly involved in the cisplatin resistance of common types of solid cancer

Glutathione S‑transferase isozyme alpha 1 is predominantly involved in the cisplatin resistance of common types of solid cancer

The mercapturic acid pathway

Metabolism of Strained Rings: Glutathione S-transferase–Catalyzed Formation of a Glutathione-Conjugated Spiro-azetidine without Prior Bioactivation

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