GST detoxifies many water-soluble environmental toxins, including solvents, herbicides, fungicides, and heavy metals (eg, mercury, cadmium, and lead). Defects in GST activity can contribute to fatigue
Glutathione-S-Transferases
The glutathione S-transferases (GST; EC 2.5.1.18) are a family of enzymes responsible for the metabolism of a broad range of xenobiotics and carcinogens (Mannervik, 1985). This enzyme catalyzes the reaction of glutathione with a wide variety of organic compounds to form thioethers, a reaction that is sometimes a first step in a detoxification process leading to mercapturic acid formation.
Simple info on Glutathione from Hyman:
In my practice, I test the genes involved in glutathione metabolism. These are the genes involved in producing enzymes that allow the body to create and recycle glutathione in the body. These genes have many names, such as GSTM1, GSTP1 and more.
Nearly all my very sick patients are missing this function. The one-third of our population that suffers from chronic disease is missing this essential gene. That includes me.
These genes impaired in some people for a variety of important reasons. We humans evolved in a time before the 80,000 toxic industrial chemicals found in our environment today were introduced into our world, before electromagnetic radiation was everywhere and before we polluted our skies, lakes, rivers, oceans and teeth with mercury and lead.
That is why most people survived with the basic version of the genetic detoxification software encoded in our DNA, which is mediocre at ridding the body of toxins. At the time humans evolved we just didn’t need more. Who knew we would be poisoning ourselves and eating a processed, nutrient-depleted diet thousands of years later?
Because most of us didn’t require additional detoxification software, almost of half of the population now has a limited capacity to get rid of toxins. These people are missing GSTM1 function — one of the most important genes needed in the process of creating and recycling glutathione in the body.
Nearly all my very sick patients are missing this function. The one-third of our population that suffers from chronic disease is missing this essential gene. That includes me. Twenty years ago I became mercury poisoned and suffered from chronic fatigue syndrome due to this very problem. My GSTM1 function was inadequate and I didn’t produce enough glutathione as a result. Eventually, my body broke down and I became extremely ill …
This is the same problem I see in so many of my patients. They are missing this critical gene and they descend into disease as a result. Let me explain how this happens …
The Importance of Glutathione in Protecting Against Chronic Illness
Glutathione is critical for one simple reason: It recycles antioxidants. You see, dealing with free radicals is like handing off a hot potato. They get passed around from vitamin C to vitamin E to lipoic acid and then finally to glutathione which cools off the free radicals and recycles other antioxidants. After this happens, the body can “reduce” or regenerate another protective glutathione molecule and we are back in business.
However, problems occur when we are overwhelmed with too much oxidative stress or too many toxins. Then the glutathione becomes depleted and we can no longer protect ourselves against free radicals, infections, or cancer and we can’t get rid of toxins. This leads to further sickness and soon we are in the downward spiral of chronic illness.
But that’s not all. Glutathione is also critical in helping your immune system do its job of fighting infections and preventing cancer. That’s why studies show that it can help in the treatment of AIDS.(i)
Glutathione is also the most critical and integral part of your detoxification system. All the toxins stick onto glutathione, which then carries them into the bile and the stool — and out of your body.
And lastly, it also helps us reach peak mental and physical function. Research has shown that raised glutathione levels decrease muscle damage, reduce recovery time, increase strength and endurance and shift metabolism from fat production to muscle development.
If you are sick or old or are just not in peak shape, you likely have glutathione deficiency.
In fact, the top British medical journal, the Lancet, found the highest glutathione levels in healthy young people, lower levels in healthy elderly, lower still in sick elderly and the lowest of all in the hospitalized elderly. (ii)
Keeping yourself healthy, boosting your performance, preventing disease and aging well depends on keeping your glutathione levels high. I’ll say it again … Glutathione is so important because it is responsible for keeping so many of the keys to UltraWellness optimized.
It is critical for immune function and controlling inflammation. It is the master detoxifier and the body’s main antioxidant, protecting our cells and making our energy metabolism run well.
And the good news is that you can do many things to increase this natural and critical molecule in your body. You can eat glutathione-boosting foods. You can exercise. And you can take glutathione-boosting supplements. Let’s review more specifics about each.
9 Tips to Optimize your Glutathione Levels
These 9 tips will help you improve your glutathione levels, improve your health, optimize your performance and live a long, healthy life.
Eat Foods that Support Glutathione Production
1. Consume sulfur-rich foods. The main ones in the diet are garlic, onions and the cruciferous vegetables (broccoli, kale, collards, cabbage, cauliflower, watercress, etc.).
2. Try bioactive whey protein. This is great source of cysteine and the amino acid building blocks for glutathione synthesis. As you know, I am not a big fan of dairy. But this is an exception — with a few warnings. The whey protein MUST be bioactive and made from non-denatured proteins (“denaturing” refers to the breakdown of the normal protein structure). Choose non-pasteurized and non-industrially produced milk that contains no pesticides, hormones, or antibiotics. Immunocal is a prescription bioactive non-denatured whey protein that is even listed in the Physician’s Desk Reference.
Exercise for Your Way to More Glutathione
3. Exercise boosts your glutathione levels and thereby helps boost your immune system, improve detoxification and enhance your body’s own antioxidant defenses. Start slow and build up to 30 minutes a day of vigorous aerobic exercise like walking or jogging, or play various sports. Strength training for 20 minutes 3 times a week is also helpful.
Take Glutathione Supporting Supplements
One would think it would be easy just to take glutathione as a pill, but the body digests protein — so you wouldn’t get the benefits if you did it this way. However, the production and recycling of glutathione in the body requires many different nutrients and you CAN take these. Here are the main supplements that need to be taken consistently to boost glutathione. Besides taking a multivitamin and fish oil, supporting my glutathione levels with these supplements is the most important thing I do every day for my personal health.
4. N-acetyl-cysteine. This has been used for years to help treat asthma and lung disease and to treat people with life-threatening liver failure from Tylenol overdose. In fact, I first learned about it in medical school while working in the emergency room. It is even given to prevent kidney damage from dyes used during x-ray studies.
5. Alpha lipoic acid. This is a close second to glutathione in importance in our cells and is involved in energy production, blood sugar control, brain health and detoxification. The body usually makes it, but given all the stresses we are under, we often become depleted.
6. Methylation nutrients (folate and vitamins B6 and B12). These are perhaps the most critical to keep the body producing glutathione. Methylation and the production and recycling of glutathione are the two most important biochemical functions in your body. Take folate (especially in the active form of 5 methyltetrahydrofolate), B6 (in active form of P5P) and B12 (in the active form of methylcobalamin).
7. Selenium. This important mineral helps the body recycle and produce more glutathione.
8. A family of antioxidants including vitamins C and E (in the form of mixed tocopherols), work together to recycle glutathione.
9. Milk thistle (silymarin) has long been used in liver disease and helps boost glutathione levels.
SOURCE:
http://drhyman.com/blog/2010/05/19/glutathione-the-mother-of-all-antioxidants/
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More Science about Glutathione:
Cytosolic and membrane-bound forms of glutathione S-transferase are encoded by two distinct supergene families. At present, eight distinct classes of the soluble cytoplasmic mammalian glutathione S-transferases have been identified: alpha, kappa, mu, omega, pi, sigma, theta and zeta. This gene encodes a glutathione S-transferase that belongs to the mu class. The mu class of enzymes functions in the detoxification of electrophilic compounds, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress, by conjugation with glutathione. The genes encoding the mu class of enzymes are organized in a gene cluster on chromosome 1p13.3 and are known to be highly polymorphic.
These genetic variations can change an individual's susceptibility to carcinogens and toxins as well as affect the toxicity and efficacy of certain drugs. Null mutations of this class mu gene have been linked with an increase in a number of cancers, likely due to an increased susceptibility to environmental toxins and carcinogens. Multiple protein isoforms are encoded by transcript variants of this gene. [provided by RefSeq, Jul 2008]
Another mechanism that may detoxify carcinogenic epoxides is conjugation with glutathione. This reaction can be catalyzed by cytosolic GSTs (Sheehan et al. 2001; Hayes et al. 2005), which are dimeric. Seven classes (alpha, mu, pi, sigma, theta, omega, and zeta) exist in mammalian species (Sheehan et al. 2001), and at least 16 GST subunits exist in humans. However, only four homodimeric enzymes to date have been characterized as catalysts of glutathione conjugation of tobacco smoke carcinogens (Cheng et al. 1995; Norppa et al. 1995; Wiencke et al. 1995; Jernstrom et al. 1996; Sundberg et al. 1998, 2002; Landi 2000; Verdina et al. 2001; Fustinoni et al. 2002; Sørensen et al. 2004a; Hayes et al. 2005). These enzymes are members of four GST classes: alpha (GSTA1-1), mu (GSTM1-1), pi (GSTP1-1), and theta (GSTT1-1). The protein levels of each GST vary significantly from person to person, as well as across tissues within an individual (Rowe et al. 1997; Sherratt et al. 1997; Mulder et al. 1999). Researchers have identified several polymorphisms in the genes encoding these subunits (Hayes et al. 2005). Of particular note with regard to cancer risk in smokers are the *NULL alleles for GSTM1 and GSTT1, which have decreased detoxification capacity and elevated DNA damage. GSTA1, GSTM1, and GSTT1 are expressed in the liver of persons who are not homozygous for either null phenotype; little GSTP1 is present in the liver (Rowe et al. 1997; Sherratt et al. 1997; Mulder et al. 1999). In contrast, the lung expresses higher levels of GSTP1 than those expressed by the other three subunits (Rowe et al. 1997; Sherratt et al. 1997).
GSTA1-1, GSTM1-1, and GSTP1-1 each catalyze the glutathione conjugation of a number of PAH diol epoxides (Jernstrom et al. 1996; Sundberg et al. 1998, 2002). However, the efficiencies and stereoselectivity of each of these enzymes vary with the diol epoxide substrate. For example, GSTM1-1 is a more efficient catalyst of glutathione conjugation of (+)-anti-BPDE than is either GSTA1-1 or GSTP1-1 (Sundberg et al. 1997). The GSTA1-1 and GSTP1-1 enzymes have overall Kcat/Km values for catalytic rate or turnover number that are about 3-fold lower than the value for GSTM1-1, but GSTM1-1 is almost 30-fold better as a catalyst for the conjugation of (-)-anti-BPDE (Sundberg et al. 1997). The contribution of each GST enzyme to the detoxification of PAH diol epoxides varies with the substrate and across different tissues on the basis of their expression levels. In lung tissue from smokers, levels of (+)-anti-BPDE–DNA adducts were dependent on the GSTM1 genotype (Alexandrov et al. 2002). Persons with the GSTM1 null genotype had significantly higher adduct levels than did those with the GST wild-type genotype. These data support the importance of GSTM1-1 activity in BPDE detoxification in the lung, but they do not exclude a role for GSTA1-1 and GSTP1-1 in the detoxification of this or other PAHs.
GSTM1-1 and GSTT1-1 enzymes play a key role in the conjugation of two 1,3-butadiene epoxide metabolites: 3,4-epoxybutene (EB) and diepoxybutane (DEB) (Norppa et al. 1995; Wiencke et al. 1995; Thier et al. 1996; Bernardini et al. 1998; Landi 2000; Fustinoni et al. 2002; Schlade-Bartusiak et al. 2004). The direct measurement of either GSTM1-1 or GSTT1-1 activity with these epoxide substrates has not been reported. However, several studies of sister chromatid exchange (SCE) in human lymphocyte cultures from persons with the GSTT1 null genotype support the role of GSTT1-1 in the detoxification of DEB (Norppa et al. 1995; Wiencke et al. 1995; Bernardini et al. 1998; Landi 2000; Schlade-Bartusiak et al. 2004). In conflict with these data, one study reports the increased mutagenicity of DEB in Salmonella typhimurium TA1535 expressing GSTT1-1, suggesting that the conjugation of this diepoxide is an activation pathway (Thier et al. 1996). The role of both GSTM1-1 and GSTT1-1 in the detoxification of EB is supported by a higher induction of SCE by EB in lymphocyte cultures from persons with either the GSTM1-1 or the GSTT1-1 null genotype (Uusküla et al. 1995; Bernardini et al. 1998). Although GSTs play a role in the metabolism of 1,3-butadiene, it remains unclear whether polymorphisms in GSTs modulate the carcinogenic effects of 1,3-butadiene in humans (Fustinoni et al. 2002).
One major excreted metabolite of benzene is S-PMA, which is formed from the glutathione conjugate of benzene oxide (Snyder and Hedli 1996). This glutathione conjugate may be generated both enzymatically and non-enzymatically, and it is not clear which pathway predominates. However, a number of studies on benzene exposure and toxicity have suggested a role for either GSTM1-1 or GSTT1-1 in the conjugation of benzene oxide (Hsieh et al. 1999; Verdina et al. 2001; Wan et al. 2002; Kim et al. 2004b). Researchers have not directly measured which enzyme is the better catalyst of glutathione conjugation of benzene oxide. The in vivo role of GSTT1-1 in benzene oxide detoxification is supported by a report that S-PMA levels excreted by persons exposed to benzene who carried the wild-type GSTT1* allele were higher than those of persons homozygous for the GSTT1* NULL allele (Sørensen et al. 2004b).
Ethylene oxide is also detoxified by glutathione conjugation (Brown et al. 1996). Although studies have not directly evaluated the role of specific human GSTs, evidence supports the role of GSTT1-1 as a catalyst of this reaction (Hallier et al. 1993; Fennell et al. 2000). On exposure to ethylene oxide, lymphocytes from persons with the GSTT1-1* NULL allele had higher levels of SCE than did those from persons with the wild-type allele (Hallier et al. 1993). In addition, levels of 2-hydroxyethylvaline Hb adducts were higher in smokers than in nonsmokers, because of exposure to ethylene and ethylene oxide in cigarette smoke, and were higher in smokers with the GSTT1* NULL allele than in those with the wild-type allele (Fennell et al. 2000).
Uridine-5′-Diphosphate-Glucuronosyltransferases
Conjugation with glucuronic acid is an important metabolic pathway for a number of carcinogens in tobacco smoke (Bock 1991; Hecht 2002a; Nagar and Remmel 2006). (Conjugation is the addition of a polar moiety to a metabolite to facilitate excretion.) The microsomal enzymes, UGTs, catalyze these conjugation reactions. Researchers have identified 18 human UGTs that are members of two families (UGT1 and UGT2) (Tukey and Strassburg 2000; Burchell 2003; Nagar and Remmel 2006). The UGT1A proteins are encoded by a single gene cluster, and expression of the nine members of this subfamily occurs through exon sharing. Exon 1 is unique for each UGT1A, whereas exon 2 to exon 5 are shared by all UGT1As (Tukey and Strassburg 2000). Thus, all UGT1A proteins are identical in the 245 amino acids of the carboxyl terminus encoded by exon 2 to exon 5 (Tukey and Strassburg 2000; Finel et al. 2005). In contrast, proteins from the UGT2 family are all unique gene products (Riedy et al. 2000; Tukey and Strassburg 2000). The expression of UGTs is tissue specific, and there are large differences in expression among tissues (Gregory et al. 2000, 2004; Tukey and Strassburg 2000; Wells et al. 2004). For example, UGTs 1A1, 1A3, 1A4, 1A6, and 1A9 are highly expressed in the liver; UGTs 1A7, 1A8, and 1A10 are mainly expressed in extrahepatic tissues (Tukey and Strassburg 2000; Gregory et al. 2004; Wells et al. 2004).
Aromatic amines and their N-hydroxy metabolites are glucuronidated to facilitate excretion (Bock 1991; Tukey and Strassburg 2000; Zenser et al. 2002). Glucuronidation is a detoxification reaction. Therefore, variations in the expression and catalytic efficiency of the enzymes that catalyze this reaction may influence the carcinogenicity of particular aromatic amines. In general, researchers have suggested that members of the UGT1A family contribute to the glucuronidation of these carcinogens (Orzechowski et al. 1994; Green and Tephly 1998; Tukey and Strassburg 2000; Zenser et al. 2002). However, UGT2B7 also catalyzes their glucuronidation (Zenser et al. 2002). In most cases, data support UGT1A9 as the best catalyst. For the tobacco smoke carcinogen 4-ABP, the relative catalytic efficiency of N-glucuronidation is UGT1A9>UGT1A4>UGT1A7>UGT 2B7>UGT1A6, but the catalytic efficiency of all these proteins is approximately equal to that of UGT1A1 (Zenser et al. 2002).
The phenol and diol metabolites of PAHs are primarily eliminated as glucuronide conjugates. Researchers have studied the role of specific UGTs in the metabolism of B[a]P (Bock 1991; Guillemette et al. 2000; Fang et al. 2002; Dellinger et al. 2006). Studies with UGT1A-deficient rats have implicated UGT1A enzymes in the detoxification of B[a]P (Wells et al. 2004). The glucuronidation of B[a]P-7,8-diol and 3-hydroxy-, 7-hydroxy-, and 9-hydroxy-B[a]P by heterologously expressed human UGTs has been characterized for a number of UGT1A and UGT2B enzymes (Fang et al. 2002; Dellinger et al. 2006). Among the phenols, UGT1A10 was the most efficient UGT1A catalyst of glucuronidation. UGTs 2B7, 2B15, and 2B17 all catalyzed conjugation of the three B[a]P phenols. However, the Km of the reaction for UGT2B enzymes was 2- to 250-fold higher than that for UGT1A10 (Dellinger et al. 2006). For the carcinogenic (-)-B[a]P-7,8-diol, UGT1A10 was a better catalyst of glucuronidation than was UGT1A9, and UGT2B7 did not catalyze detectable levels of glucuronidation (Fang et al. 2002), but UGT2B7 did catalyze the glucuronidation of (+)-B[a]P-7,8-diol.
In smokers, glucuronidation also plays an important role in the excretion of the NNK metabolite NNAL (Carmella et al. 2002b; Hecht 2002a). Both O-linked and N-linked NNAL glucuronide conjugates are formed (Carmella et al. 2002b). In addition, the direct detoxification of the hydroxymethyl metabolite of NNK occurs by glucuronidation in rats (Murphy et al. 1995). However, the contribution of this pathway to NNK detoxification in smokers has not been identified. In vitro studies with fibroblasts both from UGT1A-deficient and control rats have confirmed a role for UGT1A enzymes in the protection of these cells from NNK-induced micronuclei formation (Kim and Wells 1996). Human UGT1A9, UGT2B7, and UGT2B17 catalyze NNAL-O-glucuronidation, with UGT2B17 being the most active, and UGT1A4 catalyzes NNAL-N-glucuronidation (Ren et al. 2000; Wiener et al. 2004b; Lazarus et al. 2005). The rate of NNAL O- and N-glucuronidation by human liver microsomes varies significantly among persons; researchers have suggested that polymorphisms in UGT2B7 and UGT1A4 contribute to this variability (Wiener et al. 2004a).
Glucuronidation may also contribute to the detoxification of benzene (Bock 1991). In hepatocytes from rats treated with 3-methylcholanthrene to induce UGTs, phenol glucuronidation increases compared with sulfation. Glucuronide conjugates are more stable than the corresponding sulfates, and researchers have suggested the glucuronidation of phenol as a detoxification pathway (Bock 1991). However, to date, the role of glucuronidation in benzene-induced carcinogenesis has not been characterized and is poorly understood.
N-Acetyltransferases
NATs are cytosolic enzymes that catalyze the transfer of the acetyl group from acetylcoenzyme A to an acceptor molecule (Hein et al. 2000b). This transfer occurs through an enzyme intermediate in which cysteine 68 is acetylated and then deacetylated during the course of the reaction. Humans express two unique enzymes, NAT1 and NAT2, which catalyze both N- and O-acetylation reactions. Researchers have recognized the polymorphic nature of NAT2 for more than 40 years and, more recently, have identified more than 35 alleles (Hein et al. 2000b; Hein 2002). NAT1 is less well studied but is also polymorphic, and more than 25 alleles have been identified (Hein 2002; University of Louisville School of Medicine 2006). Researchers suggest that polymorphisms in both NAT1 and NAT2 influence the activation and detoxification of carcinogenic aromatic amines in tobacco smoke (Hein 2002).
The N-acetylation of aromatic amines, such as 4-ABP, is a detoxification reaction (Hein 2002). In contrast, O-acetylation of the N-hydroxy metabolites of arylamines generated by P-450 (e.g., N-hydroxy-4-ABP) is an activation reaction leading to DNA adduct formation (Hein et al. 1993, 1995; Hein 2002). NAT1 and NAT2 both catalyze each of these reactions (Hein et al. 1993). However, NAT2 is generally considered the more important catalyst of detoxification, and NAT1 is the more important catalyst of activation (Badawi et al. 1995; Hein 2002). This assumption is based on differences in the catalytic efficiency of the enzymes and their tissue distribution in humans as well as on studies with animal models (Hein et al. 1993; Hein 2002).
Studies with recombinant human NAT1 and NAT2 have described differences in the N-acetylation of 4-ABP. The apparent affinity of 4-ABP for NAT2 is significantly greater than that for NAT1, and ratios of NAT1 activity to NAT2 activity and clearance calculations support a greater role for NAT2 than for NAT1 in the N-acetylation of arylamines (Hein et al. 1993). The characterization of NAT1 as the key catalyst of the O-acetylation (i.e., activation) of aromatic amines is more speculative and is primarily driven by the tissue distribution of NAT1 (see the discussion below). No data in the literature report differences between the efficiencies of NAT1- and NAT2-catalyzed O-acetylation of aromatic amines. However, more recent studies that engineered S. typhimurium strains to over-express either NAT1 or NAT2 reported that NAT1, but not NAT2, catalyzed the genotoxic activation of N-hydroxy-4-ABP (Oda 2004). These data provide support for NAT1 as an important catalyst in the activation of this aromatic amine.
The organ and tissue distribution of NAT1 and NAT2 differ markedly (Dupret and Rodrigues-Lima 2005). The NAT2 protein is mainly expressed in the gut and liver; the NAT1 protein is expressed in the liver and a number of other tissues, including the colon and bladder. Researchers believe that aromatic amines in tobacco smoke contribute to smoking-related bladder cancer. Therefore, the potential activation of these compounds in the bladder is important in understanding the etiology of bladder cancer. Researchers have detected NAT1 activity, but not NAT2 activity, in samples of bladder tissue from smokers (Badwawi et al. 1995). In addition, DNA adduct levels measured by 32P-postlabeling correlated with NAT1 activity. These data are thus consistent with a role for NAT1 in the activation of arylamines in tobacco smoke.
Epidemiologic studies that demonstrate a modest increase in risk of bladder cancer in persons phenotypically and genotypically identified as having slow acetylation catalyzed by NAT2 further support the role of NAT2 in the detoxification of aromatic amines (Green et al. 2000; Hein et al. 2000a; Gu et al. 2005) (see “Molecular Epidemiology of Polymorphisms in Carcinogen-Metabolizing Genes” later in this chapter). A number of the NAT2 variant alleles identified in persons with slow acetylation were expressed heterologously and demonstrated a decrease in activity for both the N-acetylation of 4-ABP and O-acetylation of N-hydroxy-4-ABP, primarily because of the instability of the variant enzymes (Hein et al. 1995; Zhu et al. 2002). Both activation and detoxification would be diminished in persons expressing variant NAT2 activity, but NAT1 activity would be maintained. Studies that have characterized NAT1 proteins from a number of variants of this gene have also reported a decrease in enzyme activity (Fretland et al. 2002).
DNA Adducts and Biomarkers
Introduction
Although formation of carcinogen-DNA adducts is a well-characterized phenomenon in laboratory animals, there were no reports of analyses of DNA adducts in smokers before the mid-1980s. In the past 20 years, a large body of literature on DNA adducts in human tissues has emerged with the development of sensitive methods such as HPLC fluorescence, GC–MS, liquid chromatography (LC)–MS, electrochemical detection, 32P-postlabeling, and immunoassay. Researchers have applied all of these methods to analyze DNA adducts, producing data on these biomarkers in molecular epidemiologic studies of cancer susceptibility. Thus, a discussion of DNA adducts in human tissues also includes biomarkers of DNA adduct formation in smokers.
Characterized Adducts in the Human Lung
Available data on characterized DNA adducts in human lung tissue, the tissue most extensively investigated to date, are summarized in Table 5.2. The small number of studies reflects several difficulties in this research. First, DNA from human lung tissue is difficult to obtain. The amounts of DNA available from routine procedures, such as bronchoscopy, are generally too small for analysis of specific DNA adducts. Second, the levels of DNA adducts are generally low: between 1 in 10 million and 1 in 100 million normal DNA bases. Analyzing such small amounts of material is challenging. Nevertheless, methods such as those listed previously and in Table 5.2 were successfully applied. However, because of the limitations noted, the number of participants in most of the studies is small.
Table 5.2. DNA adducts in human lung tissue.
Table 5.2
DNA adducts in human lung tissue.
The major DNA adduct of B[a]P observed in laboratory animals is BPDE-N2-deoxyguanosine. Acid hydrolysis of DNA containing this adduct releases B[a]P-7,8,9,10-tetraol, which can be analyzed by HPLC with fluorescence detection (Rojas et al. 1998). Other BPDE-derived DNA adducts may be hydrolyzed simultaneously. This assay has been applied to lung tissue obtained during surgery (Alexandrov et al. 2002; Boysen and Hecht 2003). Compared with nonsmokers, smokers with the GSTM1 null genotype displayed higher levels of BPDE-DNA adducts in lung tissue, although this finding is based on a small number of cases (Rojas et al. 1998, 2004). BPDE-DNA adducts were detectable in 40 percent of the smokers with whole lung analyses (Boysen and Hecht 2003) and in all samples with analyses of bronchial epithelial cells (Rojas et al. 2004). When the adduct localization in genes was determined by in vitro studies, one target was seen to be at mutational hot spots in the P53 tumor-suppressor gene and the KRAS oncogene in cells (Tang et al. 1999; Feng et al. 2002).
REFERENCES:
"Modulation of human serum glutathione S-transferase A1/2 concentration by cruciferous vegetables in a controlled feeding study is influenced by GSTM1 and GSTT1 genotypes.".
http://www.ncbi.nlm.nih.gov/pubmed/19900941
Navarro SL, Chang JL, Peterson S, Chen C, King IB, Schwarz Y, Li SS, Li L, Potter JD, Lampe JW (2009). Cancer Epidemiol Biomarkers Prev. 18 (11): 2974–8. doi:10.1158/1055-9965.EPI-09-0701. PMC 2777676. PMID 19900941
In summary, cruciferous vegetable supplementation increased GSTA1/2, but the effect was most marked in GSTM1-null/GSTT1-null men.
MORE RESEARCH STUDIES:
http://omim.org/entry/138350?search=GSTM1&highlight=gstm1
In a study of liver specimens from 168 autopsies in Japanese individuals, Harada et al. (1987) found that the null allele of GST1 was more frequent in livers with hepatitis and carcinoma than in control livers. This supported the notion of Board (1981) that individuals with the null allele are exposed to elevated levels of certain electrophilic carcinogens. Click this to see references in PubMed related to the ones listed in the paragraph above.
GSTM1 deficiency may be a risk factor for cancer by providing increased sensitivity to particular chemical carcinogens (Strange et al., 1991; van Poppel et al., 1992). {25,24:Seidegard et al. (1986, 1990) found an association between the GSTM1 null phenotype and susceptibility to lung cancer. Click this to see references in PubMed related to the ones listed in the paragraph above.
Zhong et al. (1993) found a significant excess of GSTM1 null individuals among cases of colorectal cancer: 56.1% compared with the control group value of 41.8%. More than 70% of individuals with a tumor in the proximal colon were GSTM1 null. Click this to see references in PubMed related to the ones listed in the paragraph above.
Chen et al. (1996) described a method for simultaneous characterization of GSTM1 and GSTT1 (600436) and studied the genotypes in whites and blacks. The frequency of the null genotype for GSTM1 (GSTM1-) was higher in whites and that for GSTT1- was higher in blacks. The observed frequency of the 'double null' genotype was not significantly different from that predicted, assuming that the 2 polymorphisms are independent and did not differ by race or sex. Click this to see references in PubMed related to the ones listed in the paragraph above.
McLellan et al. (1997) found that 2 Saudi Arabian individuals with ultrarapid GSTM1 enzyme activity were heterozygous for a tandem GSTM1 gene duplication. They suggested that the duplication was generated as the reciprocal product of the homologous unequal crossing-over event that produces the null allele. Click this to see references in PubMed related to the ones listed in the paragraph above.
The formation of DNA and protein adducts by environmental pollutants is modulated by host polymorphisms in genes that encode metabolizing enzymes. In a study of 67 smokers, Godschalk et al. (2001) studied aromatic-DNA adduct levels in relation to polymorphisms in GSTM1, GSTT1, and NAT1 (108345) and NAT2 (612182). Adjusted for the amount of cigarettes smoked per day, DNA adduct levels were higher in GSTM1 null individuals than in GSTM1+ subjects; higher in NAT1 slow acetylators than in NAT1 fast acetylators; and associated with the NAT2 acetylator status for slow or fast acetylators. Highest DNA adduct levels were observed in slow acetylators for both NAT1 and NAT2 who also lacked the GSTM1 gene, and lowest in GSTM1+ subjects with the fast acetylator genotype for both NAT1 and NAT2. The results showed the combined effects of genetic polymorphisms at these 4 loci and indicated that, due to the complex carcinogen exposure, simultaneous assessment of multiple genotypes may identify individuals at higher cancer risk. Click this to see references in PubMed related to the ones listed in the paragraph above.
Patients with reduced ability to metabolize environmental carcinogens or toxins may be at risk of developing aplastic anemia. GST has been implicated in detoxifying mutagenic electrophilic compounds. Lee et al. (2001) investigated whether homozygous deletions of GSTM1 and GSTT1 affect the likelihood of developing aplastic anemia. They found that the incidence of GSTM1 and GSTT1 gene deletions was significantly higher for aplastic anemia patients than for healthy controls (odds ratio = 3.1, p = 0.01, and odds ratio = 3.1, p = 0.004, respectively). Among the aplastic anemia patients, 17.5% had chromosomal abnormalities at the time of diagnosis, and all aplastic anemia patients with chromosomal abnormalities showed GSTT1 gene deletions. Click this to see references in PubMed related to the ones listed in the paragraph above.
Carless et al. (2002) examined the role of GSTM1, GSTT1, GSTP1 (134660), and GSTZ1 (603758) gene polymorphisms in susceptibility to solar keratoses development. Using DNA samples from volunteers involved in the Nambour Skin Cancer Prevention Trial, allele and genotype frequencies were determined. No significant differences were detected in GSTP1 or GSTZ1 allele or genotype frequencies; however, a significant association between GSTM1 genotypes and solar keratoses development was detected, with null individuals having an approximate 2-fold increase in risk for solar keratoses development and a significantly higher increase in risk in conjunction with high outdoor exposure. Also, a difference in GSTT1 genotype frequencies was detected, although considering that multiple testing was undertaken, this was found not to be significant. Fair skin and inability to tan were found to be highly significant risk factors for solar keratoses development, with odds ratios of 18.5 (CI, 5.7-59.9) and 7.4 (CI, 2.6-21.0), respectively. Overall, GSTM1 conferred a significant increase in risk of solar keratoses development, particularly in the presence of high outdoor exposure and synergistically with phenotypic risk factors of fair skin and inability to tan. Click this to see references in PubMed related to the ones listed in the paragraph above.
Lohmueller et al. (2003) performed a metaanalysis of 301 published genetic association studies covering 25 different reported associations. For 8 of the associations, pooled analysis of follow-up studies yielded statistically significant replication of the first report, with modest estimated genetic effects. One of these 8 associations was that between GSTM1 and head/neck cancer (275355), as first reported by Trizna et al. (1995). Head/neck cancer showed association with homozygosity for a null allele of the GSTM1 gene. Click this to see references in PubMed related to the ones listed in the paragraph above.
Verlaan et al. (2003) investigated whether polymorphisms in the GSTM1, GSTT1, and GSTP1 genes modified the risk for chronic pancreatitis (167800). DNA was studied from 142 adult chronic pancreatitis patients with alcoholic (79 patients), hereditary (21 patients), or idiopathic (42 patients) origin. The rates of GSTT1 and GSTP1 genotypes did not differ between chronic pancreatitis patients and healthy controls; however, GSTM1 null alleles were significantly less common in alcoholic chronic pancreatitis patients (odds ratio = 0.56) as compared to healthy controls and to alcoholic controls. The frequency of the GSTM1 null genotype was significantly lower in alcoholic chronic pancreatitis patients, especially young female patients. Thus it appears that GSTM1 null alcohol users are less susceptible to chronic pancreatitis. The molecular change leading to the GSTM1 null phenotype is a partial gene deletion. It is associated with complete absence of GSTM1 enzyme activity. The frequency of the GSTM1 null genotype ranges from 23 to 62% in different populations around the world and is approximately 50% in Caucasians, as reviewed by Cotton et al. (2000). Click this to see references in PubMed related to the ones listed in the paragraph above.
Gilliland et al. (2004) found that GSTM1 and GSTP1 modify the adjuvant effect of diesel exhaust particles on allergic inflammation. They challenged ragweed-sensitive patients intranasally with allergen alone and with allergen plus diesel exhaust particles, and found that individuals with GSTM1 null or GSTP1 ile105 wildtype genotypes showed significant increases in IgE and histamine after challenge with diesel exhaust particles and allergens; the increase was largest in patients with both the GSTM1 null and GSTP1 ile/ile genotypes. Click this to see references in PubMed related to the ones listed in the paragraph above.
French et al. (2005) genotyped 126 children with newly diagnosed acute lymphoblastic leukemia at 16 well-characterized functional polymorphisms. The GSTM1 null polymorphism was a significant predictor of global gene expression, dividing patients based on their germline genotypes. Genes whose expression distinguished the null genotype from the non-null genotype included NBS1 (602667) and PRKR (176871). Although GSTM1 expression is concentrated in liver, it is involved in the conjugation (and thus transport, excretion, and lipophilicity) of a broad range of endobiotics and xenobiotics, which French et al. (2005) suggested could plausibly have consequences for gene expression in different tissues. Click this to see references in PubMed related to the ones listed in the paragraph above.
Observational studies have provided consistent evidence for a protective role of vegetable consumption against lung cancer, with the evidence being most apparent for green cruciferous vegetables such as broccoli and cabbage. Such vegetables are rich is isothiocyanates, which have been shown in animals to have strong chemopreventative properties against lung cancer (Hecht, 1996). In studies of the effect of cruciferous vegetables, a definite protective effect against any type of cancer is hard to identify, in view of the small size of studies and potential for confounding from other dietary sources. Brennan et al. (2005) addressed the problem of confounding by adopting a mendelian randomization approach. Isothiocyanates are thought to be eliminated by glutathione-S-transferase enzymes, most notably GSTM1 and GSTT1 (600430). Both GSTM1 and GSTT1 genes have null alleles with homozygous null phenotypes, resulting in no enzyme being produced. Individuals who are homozygous for the inactive form of either or both genes probably have higher isothiocyanate concentrations because of their reduced elimination capacity. Furthermore, and implicit in the mendelian randomization approach, the roles of GSTM1 and GSTT1 genes are likely to be independent of other dietary or lifestyle factors. To investigate the role of cruciferous vegetable consumption in the prevention of lung cancer in interaction with GST genotypes, Brennan et al. (2005) investigated this relation in a case-control study of 2,141 cases and 2,168 controls in 6 countries of central and eastern Europe, a region that has traditionally high rates of cruciferous vegetable consumption. Weekly consumption of cruciferous vegetables protected against lung cancer in those who were GSTM1-null (odds ratio = 0.67), GSTT1-null (odds ratio = 0.63), or both (odds ratio = 0.28). No protective effect was seen in people who were both GSTM1- and GSTT1-positive. Similar protective results were noted for consumption of cabbage and a combination of broccoli and brussels sprouts. Click this to see references in PubMed related to the ones listed in the paragraph above.
Through a genomewide association study, Huang et al. (2009) identified a significant association between
rs366631, a single-nucleotide polymorphism (SNP) approximately 11 kb downstream of the GSTM1 gene, and GSTM1 expression. Utilizing lymphoblastoid cell lines derived from International HapMap Consortium CEU and YRI populations, the authors determined that the
rs366631 SNP is a nonpolymorphic site. The false genotyping call arose from sequence homology, a common GSTM1 region deletion, and a non-specific genotyping platform used to identify the SNP. However, the HapMap call for
rs366631 genotype is an indicator of GSTM1 upstream region deletion. Furthermore, this upstream deletion can be used as a marker of GSTM1 gene deletion. More than 75% of the Caucasian (CEU) samples exhibited GSTM1 deletion, and none contained 2 copies of GSTM1. In contrast, up to 25% of African (YRI) samples were found to have 2 copies of GSTM1. The authors concluded that
rs366631 is a pseudo-SNP that can be used as a GSTM1 deletion marker. Click this to see references in PubMed related to the ones listed in the paragraph above.
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