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Glutathione S-transferase genotype

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Related terms
Background
Methods
Research
Implications
Limitations
Safety
Future research
Author information
Bibliography

Related Terms
  • Biomarker, cancer susceptibility, chemotherapy resistance, detoxification, DNA sequencing, electrophiles, glutathione S-transferase, GST, MAPEG, membrane associated proteins in eicosanoid and glutathione metabolism, PCR, polymerase chain reaction, polymorphism, redox reaction, restriction fragment length polymorphism, RFLP, susceptibility.

Background
  • Glutathione S-transferase (GST) is a family of enzymes with a vital role as catalysts (a compound which aids a chemical reaction) in the detoxification of poisonous substances. The genes which code for the GST family are located on multiple chromosomes (supergenes) and variations in these genes (polymorphisms) are associated with the development of several diseases such as cancer, Parkinson's disease, and asthma.
  • Forms and expression of GST: The GST enzyme system is expressed in the majority of life forms. It was first identified and characterized in the 1960s, and GSTs have since been classified as cytosolic (within the cytoplasm or cell fluid) or membrane bound based on their presence within cells or cell organelles. Cytosolic GST families or classes are lableled alpha, mu, pi, theta, kappa, and sigma. At least two membrane-bound human GSTs have been identified; they also belong to the 'membrane associated proteins in eicosanoid and glutathione metabolism' (MAPEG) family of cell-membrane proteins.
  • GSTs are expressed differently throughout the body and each class possesses a unique catalytic activity profile for a range of toxic chemicals. For example, the pi class is widely distributed in the body and is the only GST expressed in the colon (a part of large intestine). The alpha class of GSTs is expressed predominantly in the liver, while the mu class of GSTs appear chiefly in the muscles, testes, brain, and lungs.
  • Function: GST catalyzes the conjugation (joining) of glutathione within a cell to a great number of chemical compounds. GST also catalyzes many biological reduction-oxidation (redox) reactions. Redox reactions are a class of chemical transformations which involve a change in the oxidative status of the involved reactants, often through the transfer of electrons. Toxic biochemical substances, such as free radicals and epoxides, from both internal or external sources, are damaging to cells and can cause disease. These toxic substances are neutralized by biochemical reactions (conjugation and redox reactions) catalyzed by GST enzymes, thereby protecting the body from harm.

Methods
  • Glutathione S-transferase (GST) genes code for enzymes that play a vital role as catalysts in biochemical reactions that neutralize toxic compounds. The detoxification process prevents damage to cells thereby preventing the development of certain disorders; mutations in GST genes may increase the risk of developing diseases such as cancer, Parkinson's disease, and asthma. Mutations in GST genes can be detected using a variety of techniques, some of which are outlined below.
  • Restriction fragment length polymorphism (RFLP) analysis: RFLP analysis is a molecular laboratory technique in which DNA from a sample is cleaved (cut) into fragments by enzymes called restriction endonucleases. These enzymes cut the DNA sequences at specific sites (recognition restriction sites) resulting in fragments of DNA of characteristic lengths.
  • The fragmented DNA strands are separated based on their size and electric charges using a technique called gel electrophoresis. The separated DNA fragments are then paired with complementary sequences of DNA called probes. These probes are of sequences that are known to be complementary to only specific DNA fragments i.e., the target sequence to which it will bind. These special probes are tagged with a radioactive dye, facilitating detection by autoradiography. Autoradiography is a technique wherein target substances are tagged with radioactive molecules which can be then be visualized on film.
  • RFLP analysis is a slow and difficult technique requiring a large sample of DNA. However, with the development of polymerase chain reaction (PCR), a technique which can increase small quantities of biologic material so as to provide adequate specimens for further analysis, and its automation, certain limitations of RFLP analysis have been overcome. Also, advancement in detection techniques such as fluorescent imaging has facilitated RFLP analysis.
  • DNA sequencing: DNA sequencing is a process by which the precise sequence of nucleotides from a sample of DNA is determined. The most well known method of DNA sequencing is likely Sanger's method (dideoxy or chain termination method).The initial step involves the extraction of high quality DNA from the sample of interest, followed by polymerase chain reaction (PCR) in the presence of fluorescent labeled dideoxynucleotide triphosphate (ddNTP). ddNTPs are synthetic or man-made nucleotides that are structurally somewhat different from the regular nucleotides found in DNA, and function as DNA chain terminators (stop signals) during the synthesis of a DNA sequence. The end reaction product is a set of DNA sequences differing in length by one nucleotide with the last nucleotide base in each sequence being the unique, fluorescent labeled ddNTP.
  • The reaction products are then electrophoresed. Electrophoresis is a technique that uses electrical current to separate and analyze proteins and DNA via differences in electrical charge. The separated DNA fragments are then paired with complementary sequence of DNA called probes. These probes are tagged with a dye that emits luminescence facilitating the easy detection of the target sequence. These fluorescent signals are analyzed by a computer, identifying the exact sequence of DNA. The whole process is automated and the resultant DNA sequence is compared with other sequences by various computer programs, allowing for the identification of mutations in the sample DNA sequence.
  • Conventional DNA sequencing is laborious, time consuming, and expensive, but with the development and improvement of automated DNA sequencers and newer detection methods, the technique has become much more efficient and cost-effective. Some advantages of direct DNA sequencing include the precise identification of the type, location, and context of each mutation in a particular DNA sequence.

Research
  • Research has been conducted investigating the transfer of genetic GST genes into stem cells in bone marrow. These GST genes have special features that can neutralize toxic byproducts of anti-cancer drugs such as cyclophosphamide, and it is hoped that successful transplantation of these genes will allow increased use of chemotherapeutic drugs with fewer side-effects.
  • Recent studies have found that certain cancers are resistant to chemotherapeutic drugs. It has been determined that this may be due to over-expression (excessive production) of certain GST enzymes caused by polymorphisms in the GST genes; the drugs are processes by GST before they can act on cancer cells. This information has been used to improve management of cancers using alternative forms of drugs and treatments.
  • Several newer drugs, especially those used in the treatment of cancer, are currently being studied to understand their interactions with GST enzymes in the hopes that more effective drugs can be found.

Implications
  • Glutathione S-transferase genes encode for enzymes which protect cells and DNA from a wide array of compounds. As such, mutations or polymorphisms which alter or diminish GST enzyme expression or function can have implications for disease risk and the ability to process medications such as those used in the treatment of cancer.
  • Cancer susceptibility: Compounds processed by GST gene products include a vast number of toxic substances that cause genetic damage and cancer. Particular forms of GST gene products may not detoxify these mutagens and carcinogens resulting in increased susceptibility to certain cancers. For example, some mutations in the GSTM1 gene result in a GSTM1 deficiency, which is associated with a moderate increase in the risk of lung and bladder cancers. A polymorphism in GSTM3 is associated with certain skin cancers and laryngeal carcinoma (cancer of respiratory tract), particularly in caucasions. Persons with mutations in the GSTT1 gene often develop brain tumors. GSTP1 gene polymorphisms are also associated with an increased predisposition to testicular, oropharyngeal (mouth and throat), and bladder cancers, as well as teratomas (a kind of tumor).
  • Tolerance to chemotherapy: Chemotherapy refers to drugs or agents used in the treatment of cancer. Often these drugs have toxic side effects. Persons with GST gene polymorphisms that cause higher GST enzyme levels may break down and detoxify the chemotherapeutic agents and their metabolites more rapidly than those with lower GST enzyme levels. This may lead to reduced side effects (better tolerance) of chemotherapeutic drugs. For example, chemotherapeutic drugs used in the treatment of acute myeloid leukemia (AML), which is a form of blood cancer, are well tolerated in individuals with certain GST polymorphisms that produce higher GST enzymes, and have better clinical outcomes. However, the higher GST enzyme levels may metabolize the chemotherapeutic drugs too rapidly, before the drugs can act on the cancer cells, leading to an diminished therapeutic effect.
  • Susceptibility to other diseases: Exposure to some toxins, such as those inhaled from cigarette smoke which can cause damage blood vessels, is associated with heart attacks. Other damaging substances, like the products of oxidative stress (such as free radicals or oxidants) are associated with the development of certain diseases including asthma and Parkinson's disease. Oxidative stress refers to damaging byproducts released as part of the body's normal biochemical processes that are not adequately detoxified. Accumulated damage from oxidative stress has been associated with many of the signs of aging. Certain GST gene polymorphisms determine the level and type of GST enzymes that detoxify these toxic chemicals, thus certain of the GST polymorphisms associated with low levels of GST enzymes may increase the risk of disease or cellular damage related to oxidative stress.
  • Biomarkers: An individual's GST genotype may also be utilized as a biomarker for certain diseases. For example, GSTP1 gene methylation has been associated with the development of prostate cancer and its progression. Methylation refers to the addition of a methyl group (a combination of one carbon atom and three hydrogen atoms) at a particular spot on a section of DNA during the development of an organism, which can result in the loss of gene function. Hence, detection and quantification of GSTP1 methylation can be used as a diagnostic as well as a prognostic (predictive) biomarker for prostate cancer.

Limitations
  • Despite advancing understanding and technique, our ability to manipulate genes in humans remains limited. Therefore, the investigation, treatment, and repair of genetic defects related to GST remains difficult. A great deal of additional research remains to be done.

Safety




Future research
  • Individual glutathione S-transferase (GST) gene polymorphisms that are associated with an increased risk of cancer and other diseases are relatively low in the general population. Hence, large population studies are required to fully characterize the various combinations of polymorphisms causing detrimental changes in the GST enzyme. Further studies are also required to generate the risk profile for various diseases, when exposed to natural and synthetic chemicals in the diet and environment.
  • Additional research is also necessary to identify drugs which can reach their targets more effectively by circumventing GST detoxification safely.

Author information
  • This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

Bibliography
  1. Girisha KM, Gilmour A, Mastana S, et al. T1 and M1 polymorphism in glutathione S-transferase gene and coronary artery disease in North Indian population. Indian J Med Sci. 2004 Dec;58(12):520-6.
  2. Jeronimo C, Usadel H, Henrique R, et al. Quantitation of GSTP1 methylation in non-neoplastic prostatic tissue and organ-confined prostate adenocarcinoma. J Natl Cancer Inst. 2001 Nov 21;93(22):1747-52.
  3. Kim JH, Park SG, Lee KH, et al. GSTM1 and GSTP1 polymorphisms as potential factors for modifying the effect of smoking on inflammatory response. J Korean Med Sci. 2006 Dec;21(6):1021-7.
  4. Mannervik B, Board PG, Hayes JD, et al. Nomenclature for mammalian soluble glutathione transferases. Methods Enzymol. 2005;401:1-8.
  5. National Center for Biotechnology Information: OMIM.
  6. Natural Standard: The Authority on Integrative Medicine.
  7. Ramsay HM, Harden PN, Reece S, et al. Polymorphisms in glutathione S-transferases are associated with altered risk of nonmelanoma skin cancer in renal transplant recipients: a preliminary analysis J Invest Dermatol. 2001 Aug;117(2):251-5.
  8. Singh M, Shah PP, Singh AP, et al. Association of genetic polymorphisms in glutathione S-transferases and susceptibility to head and neck cancer. Mytat Res. 2008 Feb 1;638(1-2):184-94. Epub 2007 Oct 16.
  9. Strange RC, Jones PW, Fryer AA. Glutathione S-transferase: genetics and role in toxicology. Toxicol Lett. 2000 Mar 15;112-113:357-63.
  10. Tamer L, Calikoglu M, Ates NA, et al. Glutathione-S-transferase gene polymorphisms (GSTT1, GSTM1, GSTP1) as increased risk factors for asthma Respirology. 2004 Nov;9(4):493-8.

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The information in this monograph is intended for informational purposes only, and is meant to help users better understand health concerns. Information is based on review of scientific research data, historical practice patterns, and clinical experience. This information should not be interpreted as specific medical advice. Users should consult with a qualified healthcare provider for specific questions regarding therapies, diagnosis and/or health conditions, prior to making therapeutic decisions.

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