Mammalian class theta GST and differential susceptibility to carcinogens: a review
Introduction
The glutathione S-transferases (GSTs) are known to catalyze the conjugation of glutathione (GSH) with different species of electrophilic compounds. GSTs are an important part of the cellular detoxification system and, perhaps, evolved to protect cells against reactive oxygen metabolites. These proteins are found in all eukaryotic and prokaryotic systems, in the cytoplasm, in the microsomes and in mitochondria [1], [2]. The soluble GSTs exist as dimeric proteins of approximately 25 kDa, and the sequences and the known three-dimensional (3D) structures suggest that these proteins share a common ancestry, though the precise details of their evolution remain obscure. They are expressed at high levels in mammalian liver constituting up to 4% of the total soluble proteins [3], and at least seven distinct classes of soluble GSTs have been identified thus far: alpha (α), mu (μ), pi (π), sigma (σ), theta (θ), kappa (κ), and zeta (ζ). This classification is in accordance with the substrate specificity, chemical affinity, structure, aminoacid sequence and kinetic behavior of the enzyme.
Many excellent reviews have been published on GSTs. The present review focuses on the theta class. In comparison to other classes, the theta class has been discovered quite recently, due to the inability of GSH affinity matrices to retain the enzyme and the easy loss of activity during the purification steps [4]. Theta is one of the most interesting GSTs in terms of evolution, biochemistry, polymorphic allelism in humans, ethnical differences, and influence on human cancer risks. The theta class is so far one of the best characterized GSTs with regard to its role in the processes occurring between exposure to mutagens and the induction of DNA damage leading to mutations and cancer. These features of the GST theta class are reviewed in the present paper.
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Nomenclature
Several different nomenclatures have been adopted during the years as new GSTs were discovered. For example, the subunit of the murine GST theta used to be called “Yrs”, whereas “GST 12” and “GST 5” were two GSTs theta found in the rat. Because soluble GSTs are formed by two identical subunits, the active forms of those GST theta enzymes were called GST Yrs–Yrs, GST 5–5, or GST 12–12 [4], [5], [6], [7]. A heterodimeric form composed by the subunits Yrs and Yrs′, was also reported in the
Chromosomal location
Human GSTT1 and GSTT2 genes were colocalized, by cell–cell hybridization, in the same chromosomic region on human chromosome 22 and, by in situ hybridization, to the subband 22q11.2 [11], [12]. The absence of other regions of hybridization suggested that there are no closely related sequences scattered throughout the genome or that, if there are, they must be clustered nearby [11]. The syntheny of GSTT1 and GSTT2 genes is conserved in the mouse. The mGSTT1 gene was found, by in situ
Description
In humans, glutathione-dependent conjugation of halomethanes, such as DCM, is dimorphic, with “conjugator” and “non-conjugator” phenotypes [60]. These phenotypes are due to a genetic polymorphism occurring in the human GSTT1 gene [19]. The polymorphism consists of a deletion of the whole gene or part of it, resulting in the lack of active GSTT1-1 enzyme, easily detectable with PCR-based assays or with hybridization-based methods [61], [62]. The genotype with the homozygous deletion of the GSTT1
Expression in different tissues
The class theta is highly expressed in human adult liver but not in the fetal liver [79], [80]. It is expressed in erythrocytes, lung, kidney, brain, skeletal muscles, heart, small intestine, and spleen [15], [80], as well as in the colon mucosal cytosol [9]. In comparison to other GSTs, such as mu and phi, the activity of GST theta in lymphocytes is undetectable [15]. Studies on humans, rats and mice show a similar pattern of tissue expression, with the highest levels in liver, and the lowest
Substrates for GST theta
Among the known substrates processed by GST theta, dichloromethane (DCM) is one of the most thoroughly studied [4]. The fact that mammalian GST theta can efficiently metabolize DCM, producing formaldehyde without consuming GSH, is a reminiscence of its ancestor DCM-dehalogenase, as discussed earlier. The pathway of reaction involving GSTT1-1, GSH, and DCM is reported in detail in Fig. 7. DCM attracted the attention of researchers because it is a very effective carcinogen in mice, but not in
Association between GSTT1 polymorphism and specific diseases
As the presence of the GSTT1 gene might modulate the biological effects of genotoxicants, the GSTT1 polymorphism is suspected to affect the risk of cancer in humans, in relation to the source of exposure. In fact, it is known that increased expression of GSTT1 in rats fed with GSTT1-inducers is able to prevent some cancers, other types of cancer are increased, depending on the carcinogen employed [85]. Moreover, simulated calculations of the incidence of cancer for subjects exposed to DCM
Conclusions
In spite of the relatively recent discovery of the GSTT1-polymorphism, several studies have provided evidence to suggest that individuals lacking the GSTT1-1 enzyme might be at an increased risk of cancer of different organs, whereas evidence that GSTT1-1 positive individuals have an increased risk of cancer to exposure to halogenated compounds are rather limited. Since the GSTT1-null genotype is highly associated with BCC of the skin (not related to UV-light exposure) and with brain tumors, it
Acknowledgments
S. Landi acknowledges the support of a Research Associate Award from the National Research Council, US National Academy of Sciences. This manuscript was reviewed by the National Health and Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the agency, or the mention of trade names or commercial products constitute endorsement or recommendation for use.
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