Glutathione S-transferase: genetics and role in toxicology

doi:10.1016/S0378-4274(99)00230-1

Toxicology Letters

Volumes 112–113, 15 March 2000, Pages 357-363

https://doi.org/10.1016/S0378-4274(99)00230-1 Get rights and content

Abstract

The glutathione S-transferases (GST) are a supergene family of dimeric, enzymes that catalyse the conjugation of glutathione (GSH) to a variety of electrophiles including arene oxides, unsaturated carbonyls, organic halides and other substrates. Their importance is suggested by the finding that GST enzymes are expressed in probably all life forms. In humans, polymorphism in GST genes has been associated with susceptibility to various diseases though some recent data indicate that these genotypes modify disease phenotype. Thus, GST genotypes alone and in combination have been linked with clinical outcome.

Section snippets

Polymorphism in GST genes

Seven glutathione S-transferases (GST) gene families encoding cytosolic enzymes have been described. Examples of allelic variation have been identified in several of these families (Pemble et al., 1996, Strange and Fryer, 1999, Autrup, 1999).

GST polymorphisms and susceptibility to disease

Associations between GST genotypes and disease phenotype may reflect a link between alleles and cytogenetic damage and specific mutations in target genes. Thus, both GSTM1 and GSTT1 null cells are more susceptible to sister chromatid exchange (SCE) following exposure to various electrophiles. Presumably genotypes, alone or in combination, should identify subjects who are detoxication-deficient and consequently more likely to suffer formation of carcinogen-DNA adducts and/or mutations (Ryberg et

GST genotypes and disease outcome

There is a growing literature showing associations between GST genotype and clinical outcome. Recently, Moisio et al. (1998) described associations between GSTM1 null and GSTT1 null and location of colorectal cancers in individuals with mutation 1 in the MLH1 mismatch repair gene in Finnish kindreds. These findings suggested that GST are among an unknown number of genes (possibly including other detoxicating enzymes) that act as modifying genes that affect phenotype in monogenic colorectal

Gene–gene interactions

Studies showing associations between genotypes and susceptibility/outcome are largely based on the effects of single genes. They consider therefore, main rather than interactive effects of a gene even though the main effect could be undetectable while an interactive (epistatic) effect is large (Fig. 4). Thus, in the mouse, lung cancer susceptibility genes are often involved in one or more pairwise, interlocus interactions (Fijnemann et al., 1998). Studies on GST polymorphisms and susceptibility

Overview on GST polymorphisms and disease

While there is accumulating data indicating that GST genotypes influence disease susceptibility/outcome, the mechanism is unclear. We believe that overall the data obtained indicates they are involved in the metabolism of endogenous molecules possibly the products of oxidative stress. Current considerations include:

1.
There is no basis for predicting which cancers will be influenced by GST polymorphisms.
2.
The number of genes that mediate a clinical phenotype is not known though may be relatively

References (30)

A.H.M. Heagerty et al.
Glutathione S-transferase GSTM1 phenotypes and protection against cutaneous malignancy
Lancet
(1994)
H.W. Lo et al.
Genomic cloning of hGSTP1*C, an allelic human pi class glutathione S-transferase gene variant and functional characterization of its retinoic acid response elements
J. Biol. Chem.
(1997)
S. Xu et al.
Characterization of the human class mu glutathione S-transferase gene cluster and the GSTM1 deletion
J. Biol. Chem.
(1998)
Ali-Osman, F., Akande, A., Mao, J., 1995. Molecular cloning, characterisation and expression of novel functionally...
Autrup, H., 1999. Genetic polymorphisms in xenobiotica metabolizing enzymes as risk factors towards genotoxic response....
P.G. Board
Identification of cDNAs encoding two human alpha class glutathione transferases (GSTA3 and GSTA4) and the heterologous expression of GSTA4-4
Biochem. J.
(1998)
P.G. Board et al.
Zeta, a novel class of glutathione S-transferases in a range of species from plants to humans
Biochem. J.
(1997)
M. Coggan et al.
Structure and organization of the human theta-class glutathione S-transferase and d-dopachrome tautomerase gene complex
Biochem. J.
(1998)
R.J.A. Fijnemann et al.
High frequency of interactions between lung cancer susceptibility genes in the mouse: Mapping of Sluc5 to Sluc14
Cancer Res.
(1998)
I. Goto et al.
Prognostic significance of germ line polymorphisms of the CYP1A1 and glutathione S-transferase genes in patients with non-small cell lung cancer
Cancer Res.
(1996)

A.G. Hall et al.

Expression of mu class glutathione S-transferase correlates with event-free survival in childhood acute lymphoblastic leukaemia

Cancer Res.

(1994)

L.W. Harries et al.

Identification of genetic polymorphism at the GSTP1 locus and association with susceptibility to bladder, testicular and prostate cancer

Carcinogenesis

(1997)

M.J. Harris et al.

Polymorphism of the pi class glutathione S-transferase in normal populations and cancer patients

Pharmacogenetics

(1998)

J.D. Hayes et al.

The Glutathione S-transferase supergene family: Regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance

Crit. Rev. Biochem. Mol. Biol.

(1995)

J.D. Hayes et al.

Potential contribution of the glutathione S-transferase supergene family to resistance to oxidative stress

Free Rad. Res. Comm.

(1995)

Cited by (338)

Is placental glutathione S-Transferase (GST-P) a suitable biomarker for oral carcinogenesis: A scoping review
2023, Pathology Research and Practice
Placental Glutathione S-Transferase (GST-P) can be considered a useful marker of not only of preneoplastic lesion in rat hepatocarcinogenesis and hamster pancreatic carcinogen but also as a potential marker for premalignant and malignant lesions in cases of buccal pouch mucosa. In this context, the aim of this review is to elucidate the following question whether the GST-P is a suitable biomarker for oral carcinogenesis. A total of 16 studies were carefully selected. Our results demonstrate that GST-P expression is a useful and coherent marker for oral carcinogenesis. Regarding the samples, most studies evaluated hamsters, two evaluated GST-P expression in rats and three evaluated GST-P expression in human cells. All studies demonstrated positive findings allowing us to consider such studies reliable. In summary, our conclusion is that GST-P can be a suitable biomarker for oral carcinogenesis.
Comparison of the effects of sublethal concentrations of biofoulants, copper pyrithione and zinc pyrithione on a marine mysid - A multigenerational study
2023, Comparative Biochemistry and Physiology Part - C: Toxicology and Pharmacology
To determine the effect of copper pyrithione (CuPT) and zinc pyrithione (ZnPT), a set of acute (96 h–LC50) and chronic endpoints was studied in the marine mysid, Neomysis awatschensis. Based on the 1/10 NOECs and NOEC values calculated from 96 h–toxicity test, survival and growth, intermolt duration, feeding, and the number of newborn juveniles were measured by evaluating enzymatic activity of detoxification parameter glutathione S–transferase (GST) and cholinergic biomarker acetylcholinesterase (AChE) in the marine mysid exposed to 96 h–NOECs of CuPT and ZnPT for four weeks across three generations. Dose–dependent decreases in survival rate monitored for four weeks were observed with age–specific sensitivity in response to the 96 h–NOECs of both antifoulants. Higher growth retardation was observed with an increase in intermolt duration and inhibition of the feeding rate in CuPT–exposed mysid compared to ZnPT–exposed mysid across generations. The numbers of newborn juveniles significantly decreased at the third generation by exposure to the 96 h–NOECs of both antifoulants. GST activity was significantly inhibited in response to 96 h–NOECs of both antifoulants, whereas AChE activity was only reduced by the 96 h–NOECs of CuPT at the third generation. These results indicate that CuPT has a higher toxicity than ZnPT and even sublethal levels of CuPT and ZnPT would have detrimental effects on the maintenance of the mysid population. Finally, consistent exposure to environmentally relevant concentrations of CuPT and ZnPT can induce intergenerational toxicity in mysid.
Bifurcaria bifurcata extract exerts antioxidant effects on human Caco-2 cells
2023, Environmental Research
The present research study investigated the potential protective effect of Bifurcaria bifurcata extract on cell viability and antioxidant defences of cultured human Caco-2 cells submitted to oxidative stress induced by tert-butylhydroperoxide (tert-BOOH). Aqueous extracts were firstly characterized in terms of total phenolic contents. Concentrations of reduced glutathione (GSH) and malondialdehyde (MDA), generation of reactive oxygen species (ROS), nitric oxide (NO) production, antioxidant enzymes activities [NADPH quinone dehydrogenase 1 (NQO1) and glutathione S-transferase (GST)], caspase 3/7 activity and gene expression linked to apoptosis, proinflammation and oxidative stress signaling pathways were used as markers of cellular oxidative status. B. bifurcata extract prevented the cytotoxicity, the decrease of GSH, the increase of MDA levels and the ROS generation induced by tert-BOOH. B. bifurcata extract prevented the significant decrease of NQO1 and GST activities, and the significant increase of caspase 3/7 activity induced by tert-BOOH. B. bifurcata extract also caused an over-expression of GSTM2, Nrf2 and AKT1 transcriptors, as well as reduced ERK1, JNK1, Bax, BNIP3, NFκB1, IL-6 and HO-1 gene expressions induced by tert-BOOH suggesting an increase in cellular resistance against oxidative stress. The results of the biomarkers analyzed show that treatment of Caco-2 cells with B. bifurcata extract enhance antioxidant defences, which imply an improved cell response to an oxidative challenge. B. bifurcata extract possesses strong antioxidant properties and may be a potential effective alternative to oxidant agents in the functional food industry.
Insecticide resistance associated overexpression of two sigma GST genes assists Nilaparvata lugens to remedy oxidative stress from feeding on resistant rice variety
2022, Pesticide Biochemistry and Physiology
Insect glutathione S-transferases (GSTs) participate in detoxifying insecticides and plant metabolites in two different ways, metabolizing toxic components and remedying oxidative stress. Here in Nilaparvata lugens, a major insect pest on rice, the roles of cytosolic GSTs in resistance to insecticides and to plant defences were evaluated. The over-expression in four resistant strains indicated that NlGSTs1 and NlGSTs2 were essential to resistances to four test insecticides and H₂O₂ through an antioxidation mechanism. RNAi verified the antioxidation function of NlGSTs1 and NlGSTs2 in the resistances as a common mechanism, regardless of the structural differences among insecticides and H₂O₂. NlGSTs1 and NlGSTs2 also provided protection for N. lugens against rice defense by the same mechanism, reducing H₂O₂ levels when N. lugens were fed on the resistant rice variety Mudogo. The antioxidation activity of recombinant NlGSTs1 and NlGSTs2 is higher than their direct detoxification, which supported the ability of these two GSTs to remedy oxidative stress. For oxidative stress remediation as a common mechanism of NlGSTs1 and NlGSTs2 in both insecticide resistance and host adaptability, the development of insecticide resistance might enhance the ability of insects to remedy oxidative stress from feeding on resistant rice variety and thus to lower the resistance level of rice variety to N. lugens. The results call for careful assessment on N. lugens control when both insecticides and resistant rice variety are applied.
Evidences of the radiofrequency exposure on the antioxidant status, potentially contributing to the inflammatory response and demyelination in rat brain
2022, Environmental Toxicology and Pharmacology
Present study exhibited the oxidative potential of microwave radiation (MWR) leading to the neurodegeneration in rats. Wistar rats were exposed at 2100 MHz frequency for 4 h/day, 5 days/week/3 months. Animals were exposed at an estimated specific absorption rate (0.453 W/kg) and power density (8.237 µW/m²). After exposure irradiated group was compared with control group. Results indicated that microwave exposure significantly increased the levels of serological triglycerides and cholesterol. Oxidative stress is observed through alteration of glutathione homeostasis followed by activated inflammatory response further confirmed by pro and anti-inflammatory cytokines in the exposed group. Histopathological assessments and electron microscopic observation confirmed a significant change in the myelination pattern and cellular organelles in the brain of exposed animals. Taking everything into account it can be concluded that chronic exposure of 2100-MHz frequency caused oxidative stress, which leads to neural damage and demyelination and may affect neural communication.
Glutathione-S-transferase genetic polymorphism and risk of hepatotoxicity to antitubercular drugs in a North-African population: A case-control study
2022, Gene
GST non-functional genotypes can lead to the accumulation of toxic intermediates, resulting in liver damage and increasing susceptibility to ATDH.
To investigate the impact of GST Mu (GSTM1), GST Theta (GSTT1) null genotypes, and GST Pi (GSTP1; adenosine (A) > guanine (G), rs1695) variant allele on the development of ATDH in Tunisian patients treated with anti-tuberculosis therapy.
This was a case-control study including patients receiving anti-tuberculosis regimen. Cases (n = 23) were tuberculosis patients presenting ATDH during two months of anti-tuberculosis drug therapy. Controls (n = 30) were patients treated for tuberculosis, but presenting no ATDH. Genotyping was performed using a polymerase chain reaction-restriction fragment length polymorphism.
No statistically significant association was observed between GSTM1 and GSTT1 homozygous null genotypes, and the risk of ATDH. A statistically significant association between GSTM1 and GSTT1 double null genotypes, and the risk of ATDH was found (p = 0.033) between cases and controls. For GSTP1, the distribution of GG homozygous mutant genotype was significantly associated with ATDH compared with the wild and the transition A to G (AA + AG) genotypes.
Double deletion of GSTM1 and GSTT1 may predispose to ATDH in a Tunisian population. Moreover, GSTP1 rs1695 (A > G) genotyping can predict susceptibility to developing ATDH.

View all citing articles on Scopus

View full text

Glutathione S-transferase: genetics and role in toxicology

Abstract

Section snippets

Polymorphism in GST genes

GST polymorphisms and susceptibility to disease

GST genotypes and disease outcome

Gene–gene interactions

Overview on GST polymorphisms and disease

Lancet

J. Biol. Chem.

J. Biol. Chem.

Identification of cDNAs encoding two human alpha class glutathione transferases (GSTA3 and GSTA4) and the heterologous expression of GSTA4-4

Biochem. J.

Zeta, a novel class of glutathione S-transferases in a range of species from plants to humans

Biochem. J.

Structure and organization of the human theta-class glutathione S-transferase and d-dopachrome tautomerase gene complex

Biochem. J.

High frequency of interactions between lung cancer susceptibility genes in the mouse: Mapping of Sluc5 to Sluc14

Cancer Res.

Prognostic significance of germ line polymorphisms of the CYP1A1 and glutathione S-transferase genes in patients with non-small cell lung cancer

Cancer Res.

Expression of mu class glutathione S-transferase correlates with event-free survival in childhood acute lymphoblastic leukaemia

Cancer Res.

Identification of genetic polymorphism at the GSTP1 locus and association with susceptibility to bladder, testicular and prostate cancer

Carcinogenesis

Polymorphism of the pi class glutathione S-transferase in normal populations and cancer patients

Pharmacogenetics

The Glutathione S-transferase supergene family: Regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance

Crit. Rev. Biochem. Mol. Biol.

Potential contribution of the glutathione S-transferase supergene family to resistance to oxidative stress

Free Rad. Res. Comm.