The glutathione S-transferases (GST) represent a major group of detoxification enzymes. All eukaryotic species possess multiple cytosolic and membrane-bound GST isoenzymes, each of which displays distinct catalytic as well as noncatalytic binding properties: the cytosolic enzymes are encoded by at least five distantly related gene families (designated class alpha, mu, pi, sigma, and theta GST), whereas the membrane-bound enzymes, microsomal GST and leukotriene C, synthetase, are encoded by single genes and both have arisen separately from the soluble GST. Evidence suggests that the level of expression of GST is a crucial factor in determining the sensitivity of cells to a broad spectrum of toxic chemicals. In this article the biochemical functions of GST are described to show how individual isoenzymes contribute to resistance to carcinogens, antitumor drugs, environmental pollutants, and products of oxidative stress.A description of the mechanisms of transcriptional and posttranscriptional regulat...

The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance.

The goal of this review is to present a comprehensive survey of the many intriguing facets of creatine (Cr) and creatinine metabolism, encompassing the pathways and regulation of Cr biosynthesis an...

http://www.afboard.com/library/creatinemetabolism.pdf

Creatine and Creatinine Metabolism

The complexity of tobacco smoke leads to some confusion about the mechanisms by which it causes lung cancer. Among the multiple components of tobacco smoke, 20 carcinogens convincingly cause lung tumors in laboratory animals or humans and are, therefore, likely to be involved in lung cancer induction. Of these, polycyclic aromatic hydrocarbons and the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone are likely to play major roles. This review focuses on carcinogens in tobacco smoke as a means of simplifying and clarifying the relevant information that provides a mechanistic framework linking nicotine addiction with lung cancer through exposure to such compounds. Included is a discussion of the mechanisms by which tobacco smoke carcinogens interact with DNA and cause genetic changes--mechanisms that are reasonably well understood--and the less well defined relationship between exposure to specific tobacco smoke carcinogens and mutations in oncogenes and tumor suppressor genes. Molecular epidemiologic studies of gene-carcinogen interactions and lung cancer--an approach that has not yet reached its full potential--are also discussed, as are inhalation studies of tobacco smoke in laboratory animals and the potential role of free radicals and oxidative damage in tobacco-associated carcinogenesis. By focusing in this review on several important carcinogens in tobacco smoke, the complexities in understanding tobacco-induced cancer can be reduced, and new approaches for lung cancer prevention can be envisioned.

/pdf/tobacco-smoke-carcinogens-and-lung-cancer-151e8tf0fh.pdf

Tobacco Smoke Carcinogens and Lung Cancer

The glutathione transferases are recognized as important catalysts in the biotransformation of xenobiotics, including drugs as well as environmental pollutants. Multiple forms exist, and numerous transferases from mammalian tissues, insects, and plants have been isolated and characterized. Enzymatic properties, reactions with antibodies, and structural characteristics have been used for classification of the glutathione transferases. The cytosolic mammalian enzymes could be grouped into three distinct classes--Alpha, Mu, and Pi; the microsomal glutathione transferase differs greatly from all the cytosolic enzymes. Members of each enzyme class have been identified in human, rat, and mouse tissues. Comparison of known primary structures of representatives of each class suggests a divergent evolution of the enzyme proteins from a common precursor. Products of oxidative metabolism such as organic hydroperoxides, epoxides, quinones, and activated alkenes are possible "natural" substrates for the glutathione transferases. Particularly noteworthy are 4-hydroxyalkenals, which are among the best substrates found. Homologous series of substrates give information about the properties of the corresponding binding site. The catalytic mechanism and the active-site topology have been probed also by use of chiral substrates. Steady-state kinetics have provided evidence for a "sequential" mechanism.

Glutathione transferases--structure and catalytic activity.

Toxicity, metabolism, and impact of mycotoxins on humans and animals.

In humans, glutathione-dependent conjugation of halomethanes is polymorphic, with 60% of the population classed as conjugators and 40% as non-conjugators. We report the characterization of the genetic polymorphism causing the phenotypic difference. We have isolated a cDNA that encodes a human class Theta GST (GSTT1) and which shares 82% sequence identity with rat class Theta GST5-5. From PCR and Southern blot analyses, it is shown that the GSTT1 gene is absent from 38% of the population. The presence or absence of the GSTT1 gene is coincident with the conjugator (GSST1+) and non-conjugator (GSTT1-) phenotypes respectively. The GSTT1+ phenotype can catalyse the glutathione conjugation of dichloromethane, a metabolic pathway which has been shown to be mutagenic in Salmonella typhimurium mutagenicity tester strains and is believed to be responsible for carcinogenicity of dichloromethane in the mouse. In humans, the enzyme is found in the erythrocyte and this may act as a detoxification sink. Characterization of the GSTT1 polymorphism will thus enable a more accurate assessment of human health risk from synthetic halomethanes and other industrial chemicals.

/pdf/human-glutathione-s-transferase-theta-gstt1-cdna-cloning-and-f5bx6dij3r.pdf

Human glutathione S-transferase theta (GSTT1): cDNA cloning and the characterization of a genetic polymorphism.

Glutathione transferases (GSTs) of a novel class, which it is proposed to term Theta, were purified from rat and human liver. Two, named GST 5-5 and GST 12-12, were obtained from the rat, and one, named GST theta, was from the human. Unlike other mammalian GSTs they lack activity towards 1-chloro-2,4-dinitrobenzene and are not retained by GSH affinity matrices. Only GST 5-5 retains full activity during purification, and its activities towards the substrates 1,2-epoxy-3-(p-nitrophenoxy)propane, p-nitrobenzyl chloride, p-nitrophenethyl bromide, cumene hydroperoxide, dichloromethane and DNA hydroperoxide are 185, 86, 67, 42, 11 and 0.03 mumol/min per mg of protein respectively. Earlier preparations of GST 5-5 or GST E were probably a mixture of GST 5-5 and GST 12-12, which was largely inactive, and may also have been contaminated by less than 1% with another GSH peroxidase of far greater activity. Partial analysis of primary structure shows that subunits 5, 12 and theta are related to each other, particularly at the N-terminus, where 25 of 27 residues are identical, but have little relationship to the Alpha, Mu and Pi classes of mammalian GSTs. They do, however, show some relatedness to subunit I of Drosophila melanogaster [Toung, Hsieh & Tu (1990) Proc. Natl. Acad. Sci. U.S.A. 87, 31-35] and the dichloromethane dehalogenase of Methylobacterium DM4 [La Roche & Leisinger (1990) J. Bacteriol, 172, 164-171].

/pdf/theta-a-new-class-of-glutathione-transferases-purified-from-vwpfdrv23z.pdf

Theta, a new class of glutathione transferases purified from rat and man.

Glutathione (GSH) is a strong nucleophile which reacts well with soft electrophiles, but poorly with both weak and strong electrophiles. Weak electrophiles have low reactivity with all nucleophiles...

https://www.jstor.org/stable/pdfplus/3429581.pdf

The Role of Glutathione in Detoxication

Cytosolic glutathione S-transferases (GSTs) are a supergene family of dimeric enzymes capable of detoxifying a number of carcinogenic electrophiles. Of the numerous components of tobacco smoke, the polycyclic aromatic hydrocarbons appear to be the principal compounds that yield substrates for these enzymes, GSTM1-1 being effective with those PAH derivatives so far studied; however, the gene locus for GSTM1 is polymorphic, containing two well-characterized expressing genes and a null allele. Use of cDNA for GSTM1-1 or appropriate fragments of genomic clones as probes in Southern blots indicated that the null allele is due to the absence of GSTM1. In preliminary experiments, described here, with lung tissue from smokers, levels of 32P-postlabeled nuclease P1-enhanced DNA adducts were inversely correlated with levels of antigen cross-reacting with antibody to GSTM1-1, suggesting that initiation depends on the expression of GSTM1-1. Since similar quantities of DNA adducts and GSTM1-1 activity have been shown to occur in bronchial and peripheral lung, however, the development of malignancy, which is usually in the bronchial region, presumably depends on additional factors that bring about promotion and progression, which are not necessarily affected by GSTM1 expression. Two epidemiological studies have been carried out in which a possible correlation between the absence of GSTM1 and lung cancer incidence is considered. In the first, involving a U.S. population sample, smokers with and without lung cancer were phenotyped, and a highly significant correlation between the absence of GSTM1-1 activity and adenocarcinoma of the lung was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

The human glutathione S-transferase supergene family, its polymorphism, and its effects on susceptibility to lung cancer.

Cancer patients with weight loss showed urinary excretion of a lipid-mobilizing factor (LMF), determined by the ability to stimulate lipolysis in isolated murine epididymal adipocytes. Such bioactivity was not detectable in the urine of cancer patients without weight loss or in normal subjects. The LMF was purified using a combination of ion exchange, exclusion, and hydrophobic interaction chromatographies to give a single component of apparent M r 43,000, which showed homology in amino acid sequence with human plasma Zn-α2-glycoprotein. Both substances showed the same mobility on denaturing and nondenaturing gels and the same chymotrypsin digestion pattern, both stained heavily for carbohydrate, and they showed similar immunoreactivity. Polyclonal antisera to human plasma Zn-α2-glycoprotein was also capable of neutralization of the bioactivity of human LMF in vitro . Using competitive PCR to quantify expression of Zn-α2-glycoprotein, we found that only those tumors that were capable of producing a decrease in carcass lipid expressed mRNA for Zn-α2-glycoprotein. These results provide strong evidence to suggest that tumor production of Zn-α2-glycoprotein is responsible for the lipid catabolism seem in cancer patients.

https://cancerres.aacrjournals.org/content/canres/58/11/2353.full.pdf

David J. Meyer

Papers

Human glutathione S-transferase theta (GSTT1): cDNA cloning and the characterization of a genetic polymorphism.

Theta, a new class of glutathione transferases purified from rat and man.

The Role of Glutathione in Detoxication

The human glutathione S-transferase supergene family, its polymorphism, and its effects on susceptibility to lung cancer.

Purification and characterization of a tumor lipid-mobilizing factor