Mammalian class theta GST and differential susceptibility to carcinogens: a review.
Glutathione S-transferases (GSTs) are an important part of the cellular detoxification system and, perhaps, evolved to protect cells against reactive oxygen metabolites. Theta is considered the most ancient among the GSTs and theta-like GSTs are found in mammals, fish, insects, plants, unicellular algae, and bacteria. It is thought that an ancestral theta-gene underwent an early duplication before the divergence of fungi and animals and further duplications generated the variety of the other classes of GSTs (alpha, mu, phi, etc.). The comparison of the aminoacidic homologies among mammals suggests that a duplication of an ancient GST theta occurred before the speciation of mammals and resulted in the subunits GSTT1 and GSTT2. The ancestral GST theta has a dehalogenase activity towards several halogenated compounds, such as the dichloromethane. In fact, some aerobic and anaerobic methylotrophic bacteria can use these molecules as the sole carbon and energy source. The mammalian GST theta cannot sustain the growth of bacteria but still retains the dehalogenating activity. Therefore, although mammalian GST theta behaves as a scavenger towards electrophiles, such as epoxides, it acts also as metabolic activator for halogenated compounds, producing a variety of intermediates potentially dangerous for DNA and cells. For example, mice exposed to dichloromethane show a dose-dependent incidence of cancer via the GSTT1-1 pathway. Because GSTT1-1 is polymorphic in humans, with about 20% of Caucasians and 80% of Asians lacking the enzyme, the relationship between the phenotype and the incidence of cancer has been investigated extensively in order to detect GSTT1-1-associated differential susceptibility towards endogenous or exogenous carcinogens. The lack of the enzyme is related to a slightly increased risk of cancer of the bladder, gastro-intestinal tract, and for tobacco-related tumors (lung or oral cavity). More pronounced risks were found in males with the GSTT1-null genotype for brain diseases and skin basal cell carcinomas not related to sunlight exposures. Moreover, there was an increased risk of kidney and liver tumors in humans with the GSTT1-1 positive genotype following exposures to halogenated solvents. Interestingly, the liver and kidney are two organs that express the highest level of GST theta in the human body. Thus, the GSTT1-1 genotype is suspected to confer decreased or increased risk of cancer in relation to the source of exposure; in vitro studies, mostly conducted on metabolites of butadiene, confirm the protective action of GSTT1-1, whereas, thus far, experimental studies prove that the increasing risk is limited.
Landi
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Environmental Carcinogenesis Division, US Environmental Protection Agency, Research, Triangle Park, NC 27711, USA. landi@iarc.fr
D000595:Amino Acid Sequence; D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics; D001483:Base Sequence; D002273:Carcinogens / Q000493:pharmacokinetics*; D019281:Dimerization; D004351:Drug Resistance; D004790:Enzyme Induction; D019143:Evolution, Molecular; D005260:Female; D005787:Gene Frequency; D005796:Genes; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005982:Glutathione Transferase / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008658:Inactivation, Metabolic; D019746:Intramolecular Oxidoreductases / Q000235:genetics; D008190:Lyases / Q000737:chemistry / Q000235:genetics; D008297:Male; D008322:Mammals / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009190:Myelodysplastic Syndromes / Q000201:enzymology / Q000235:genetics; D009369:Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics; D009928:Organ Specificity; D010084:Oxidation-Reduction; D011110:Polymorphism, Genetic; D011355:Prodrugs / Q000493:pharmacokinetics; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D044469:Racial Groups / Q000235:genetics; D051381:Rats; D016415:Sequence Alignment; D017384:Sequence Deletion; D017385:Sequence Homology; D012907:Smoking / Q000009:adverse effects; D013045:Species Specificity; D013379:Substrate Specificity
D001426:Bacterial Proteins; D002273:Carcinogens; D005982:Glutathione Transferase; D019746:Intramolecular Oxidoreductases; D008190:Lyases; D011355:Prodrugs; C491107:GSTT2 protein, human; C484260:Gstt2 protein, mouse; C091152:Gstt2 protein, rat; C413545:glutathione S-transferase T1; C045224:dichloromethane dehalogenase; C042501:dopachrome isomerase