Protective role of glutathione and glutathione transferases in mutagenesis and carcinogenesis

doi:10.1016/0027-5107(88)90197-2

Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis

Volume 202, Issue 2, December 1988, Pages 343-361

https://doi.org/10.1016/0027-5107(88)90197-2 Get rights and content

Abstract

Glutathione (GSH) alone detoxifies electrophiles with an effectiveness which depends on the rate of the reaction and the concentration of GSH. If electrophiles are substrates for GSH transferase isoenzymes, the effectiveness of detoxication is much enhanced due to the increased rate of reaction and it is also independent of GSH concentration to low levels of GSH depletion, since the K_m for GSH is approximately 0.1 mM. In this paper detoxication of electrophilic metabolites of the hepatocarcinogen N-methyl-4-aminoazobenzene which are not substrates for GSH transferases and the carcinogenic electrophile derived from the hepatocarcinogen aflatoxin B₁ which is a poor substrate is compared with detoxication of electrophiles which are good substrates and which although bacterial mutagens are not carcinogenic in organs containing the appropriate GSH transferases. GSH transferases detoxify not only electrophiles derived from xenobiotics, but also endogenous electrophiles which are usually the consequence of free radical damage in the presence of oxygen to lipids and DNA and include lipid and DNA hydroperoxides and alkenals arising from the decomposition of lipid hydroperoxides.

Studies in the rat and other mammals show the GSH transferases to be dimers in which the subunits are members of a gene super-family. There are three, perhaps four multigene families namely, alpha containing subunits 1, 2, 8 and 10; mu containing subunits 3, 4 6 and 9; pi containing subunit 7 and subunits 5 and 5^∗ which are so far unassigned. Subunit 5^∗ is apparently restricted to the nucleus and is noteworthy for its activity towards DNA hydroperoxides. Studies in the human are not as advanced as in the rat but so far reveal close similarities.

The ability of GSH transferases to detoxify electrophiles is important in carcinogenesis at a number of points. They may inhibit initiation and tumour proportion, but they may be advantageous to the developing tumour cell, and may be acquired in increased amounts during malignant progression. In many tumour cells the development of lines resistant to anticancer drugs is associated with an increased expression of GSH transferases, particularly GSH transferase π in human cells.

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Interactions between nanomaterials (NMs) and coexisting contaminants are important contributors to their joint biological effects, while the reverse actions of bioresponses in determining the toxic interaction between NMs and contaminants were rarely understood. Here, we investigated the toxic interaction and mechanism between TiO₂ NMs (nTiO₂) and pentachlorophenol (PCP) in soil using the model nematode (Caenorhabditis elegans). PCP (0.5–50 mg/kg) and nTiO₂ (50–5000 mg/kg) co-exposures induced antagonistic effects on the survival, growth, and locomotion of nematodes, and the levels of ultrastructural damage and oxidative stress exhibited consistent alterations. Soil PCP concentrations changed insignificantly after the single or combined exposures, indicating a negligible direct interaction between PCP and nTiO₂ under the soil condition. Transcriptomic analysis revealed that after 50 mg/kg PCP exposure, half of differentially expressed genes were involved in epidermal collagen synthesis, while the PCP-nTiO₂ co-exposure particularly activated genes related to antistress responses and the positive regulation of physiological functions. Further biochemical analysis demonstrated the antagonistic interactions were derived from two aspects: 1) PCP-induced epidermal collagen incrassation lowered the bioaccumulation and toxicity of nTiO₂; 2) nTiO₂-activated glutathione detoxification pathway alleviated PCP-induced toxicity. These findings highlight the key role of bioresponses in determining toxic interactions between NMs and co-contaminants.
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It is concluded that diabetes mellitus induced changes in oxidative stress, phase I & II drug-metabolizing enzymes, and antioxidant enzymes activities, whereas both extracts of Trigonella stellata alleviated such changes. Alterations in cytochrome P₄₅₀ system should be considered when therapeutic drugs are administered to diabetic patients since most of xenobiotic are mainly metabolized by this system.
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However other studies did not confirm this association [22,23,27,30,31.]]. Another detoxifying enzyme glutathione S-transferase (GST) has been a subject of investigation because GSTs catalyze the conjugation of electrophilic compounds to glutathione and alkylating agents are known substrates of GSTs [32]. GSTT1 and GSTM1 encode two classes of GST enzymes and deletion of these genes is relatively common in the general population [33,34].
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