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Genetic variations in human glutathione transferase enzymes: significance for pharmacology and toxicology.

Josephy PD - Hum Genomics Proteomics (2010)

Bottom Line: Glutathione transferase enzymes (GSTs) catalyze reactions in which electrophiles are conjugated to the tripeptide thiol glutathione.Many molecular epidemiological studies have tested associations between polymorphisms (especially, deletions) of human GST genes and disease susceptibility or response to therapy.This review presents a discussion of the biochemistry of GSTs, the sources-both genetic and environmental-of interindividual variation in GST activities, and their implications for pharmaco- and toxicogenetics; particular attention is paid to the Theta class GSTs.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada N1G 2W1.

ABSTRACT
Glutathione transferase enzymes (GSTs) catalyze reactions in which electrophiles are conjugated to the tripeptide thiol glutathione. While many GST-catalyzed transformations result in the detoxication of xenobiotics, a few substrates, such as dihaloalkanes, undergo bioactivation to reactive intermediates. Many molecular epidemiological studies have tested associations between polymorphisms (especially, deletions) of human GST genes and disease susceptibility or response to therapy. This review presents a discussion of the biochemistry of GSTs, the sources-both genetic and environmental-of interindividual variation in GST activities, and their implications for pharmaco- and toxicogenetics; particular attention is paid to the Theta class GSTs.

No MeSH data available.


Related in: MedlinePlus

Organization of the human GST Theta gene region. The figure is drawn approximately to scale, based on NCBI Reference Sequence: NC_000022.10, Homo sapiens chromosome 22, GRCh37 primary reference assembly.
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fig3: Organization of the human GST Theta gene region. The figure is drawn approximately to scale, based on NCBI Reference Sequence: NC_000022.10, Homo sapiens chromosome 22, GRCh37 primary reference assembly.

Mentions: The structure of the human GST Theta region [70, 71] is remarkable (Figure 3). The GST1 and GST2 are oriented head-to-head. GSTT2B was originally referred to as a probable pseudogene, GSTT2P [70], but is now annotated as “glutathione S-transferase theta 2B (gene/pseudogene)” on the NCBI genome database. (Pseudogenes identified as GSTTP1 and GSTTP2 are also annotated on the database but have not been studied in detail.) The GSTT2, DDT, DDT-L, and GSTT2B genes are found within a 61 kb inverted repeat sequence which was recently discovered to be the site of a prevalent (allele frequency approximately 50%) deletion polymorphism that spans the entire GSTT2B gene [71]. Additional characteristics of this previously unknown deletion polymorphism may have important implications for pharmacogenetic studies of the GST Theta genes. Surprisingly, deletion of the GSTT2B gene appears to result in greatly reduced expression of the GSTT2 gene, by an as-yet unknown mechanism; the GSTT2B deletion shows linkage disequilibrium with the much-studied GSTT1 deletion polymorphism, with a very low frequency of alleles carrying deletions of both GSTT1 and GSTT2B [71]. Furthermore, the extent of linkage disequilibrium was very different among three population samples examined: very strong in a northern/western European ancestry sample, strong in a Japanese-Chinese sample, but absent in a Nigerian Yoruba sample [71]. Further investigation of the molecular genetics of human GSTs is very much needed.


Genetic variations in human glutathione transferase enzymes: significance for pharmacology and toxicology.

Josephy PD - Hum Genomics Proteomics (2010)

Organization of the human GST Theta gene region. The figure is drawn approximately to scale, based on NCBI Reference Sequence: NC_000022.10, Homo sapiens chromosome 22, GRCh37 primary reference assembly.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2958679&req=5

fig3: Organization of the human GST Theta gene region. The figure is drawn approximately to scale, based on NCBI Reference Sequence: NC_000022.10, Homo sapiens chromosome 22, GRCh37 primary reference assembly.
Mentions: The structure of the human GST Theta region [70, 71] is remarkable (Figure 3). The GST1 and GST2 are oriented head-to-head. GSTT2B was originally referred to as a probable pseudogene, GSTT2P [70], but is now annotated as “glutathione S-transferase theta 2B (gene/pseudogene)” on the NCBI genome database. (Pseudogenes identified as GSTTP1 and GSTTP2 are also annotated on the database but have not been studied in detail.) The GSTT2, DDT, DDT-L, and GSTT2B genes are found within a 61 kb inverted repeat sequence which was recently discovered to be the site of a prevalent (allele frequency approximately 50%) deletion polymorphism that spans the entire GSTT2B gene [71]. Additional characteristics of this previously unknown deletion polymorphism may have important implications for pharmacogenetic studies of the GST Theta genes. Surprisingly, deletion of the GSTT2B gene appears to result in greatly reduced expression of the GSTT2 gene, by an as-yet unknown mechanism; the GSTT2B deletion shows linkage disequilibrium with the much-studied GSTT1 deletion polymorphism, with a very low frequency of alleles carrying deletions of both GSTT1 and GSTT2B [71]. Furthermore, the extent of linkage disequilibrium was very different among three population samples examined: very strong in a northern/western European ancestry sample, strong in a Japanese-Chinese sample, but absent in a Nigerian Yoruba sample [71]. Further investigation of the molecular genetics of human GSTs is very much needed.

Bottom Line: Glutathione transferase enzymes (GSTs) catalyze reactions in which electrophiles are conjugated to the tripeptide thiol glutathione.Many molecular epidemiological studies have tested associations between polymorphisms (especially, deletions) of human GST genes and disease susceptibility or response to therapy.This review presents a discussion of the biochemistry of GSTs, the sources-both genetic and environmental-of interindividual variation in GST activities, and their implications for pharmaco- and toxicogenetics; particular attention is paid to the Theta class GSTs.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada N1G 2W1.

ABSTRACT
Glutathione transferase enzymes (GSTs) catalyze reactions in which electrophiles are conjugated to the tripeptide thiol glutathione. While many GST-catalyzed transformations result in the detoxication of xenobiotics, a few substrates, such as dihaloalkanes, undergo bioactivation to reactive intermediates. Many molecular epidemiological studies have tested associations between polymorphisms (especially, deletions) of human GST genes and disease susceptibility or response to therapy. This review presents a discussion of the biochemistry of GSTs, the sources-both genetic and environmental-of interindividual variation in GST activities, and their implications for pharmaco- and toxicogenetics; particular attention is paid to the Theta class GSTs.

No MeSH data available.


Related in: MedlinePlus