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(The FASEB Journal. 2001;15:752-757.)
© 2001 FASEB

Increased DNA alterations in atherosclerotic lesions of individuals lacking the GSTM1 genotype

ALBERTO IZZOTTI*, CRISTINA CARTIGLIA*, JOELLEN LEWTAS{dagger} and SILVIO DE FLORA*1

* Department of Health Sciences, University of Genoa, Italy; and
{dagger} U.S. Environmental Protection Agency, Seattle, Washington, USA

1Correspondence: Department of Health Sciences, University of Genoa, via A. Pastore 1, I-16132 Genoa, Italy. E-mail: sdf{at}unige.it


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Reduced glutathione (GSH) plays a critical role as an intracellular defense system providing detoxification of a broad spectrum of reactive species and their excretion as water-soluble conjugates. Conjugation of GSH with electrophiles is catalyzed by GSH S-transferases (GST), which constitute a broad family of phase II isoenzymes. Two of the GST encoding genes, GSTM1 (µ) and GSTT1 ({theta}), have a null genotype due to their homozygous deletion that results in lack of active protein. Polymorphisms within GSTT1 and especially GSTM1 have often been associated with cancer in various organs as well as with elevated levels of DNA adducts in various cell types. We recently demonstrated that DNA adducts are consistently detectable in smooth muscle cells (SMC) of human abdominal aorta affected by atherosclerotic lesions. Here we provide evidence that levels of adducts to SMC DNA from atherosclerotic lesions are consistently increased in individuals having the null GSTM1 genotype, whereas no association was established with the GSTT1 polymorphism. The influence of GSTM1 deletion was better expressed in never-smokers and ex-smokers than in current smokers. These findings bear relevance to the epidemiology of atherosclerosis and suggest that metabolic polymorphisms may contribute to the interindividual variability in susceptibility not only to carcinogens, but also to DNA binding atherogens.—Izzotti, A., Cartiglia, C., Lewtas, J., De Flora, S. Increased DNA alterations in atherosclerotic lesions of individuals lacking the GSTM1 genotype.


Key Words: metabolic polymorphisms • glutathione S-transferases • smooth muscle cells • DNA adducts


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
THE GLUTATHIONE (GSH) SYSTEM provides a major system that plays a protective role against a broad variety of toxic agents involved in the pathogenesis of several chronic degenerative diseases (1) . Most of the biological functions of this tripeptide ({gamma}-glutamyl-L-cysteinyl glycine) depend on the reactivity of the thiol group of its cysteinyl residue (2) . The reaction rate of GSH with electrophiles is greatly enhanced by GSH S-transferases (GST), which catalyze conjugation processes resulting in detoxification and excretion of water-soluble conjugates (3 , 4) . Genetic polymorphisms have been detected within this broad family of phase II isoenzymes. In particular, two of the GST encoding genes, identified as GSTM1 (µ) and GSTT1 ({theta}), have a null genotype in humans due to the deletions of both paternal and maternal alleles, resulting in lack of active proteins (5) .

Polymorphisms within GSTT1 and especially GSTM1 have often be associated with cancer in various organs (reviewed in refs 6 7 8 ), although the results of the many available epidemiologic studies suffer from lack of consistency, also due to heterogeneity in their design and conduction (6) . In addition, the null GSTM1 genotype has been associated with elevated levels of DNA adducts, which are promutagenic and procarcinogenic lesions (9) , in leukocytes, bronchi, and lung tissue (see, e.g., refs 10 11 12 13 ).

We recently demonstrated that DNA adducts are consistently detectable in smooth muscle cells (SMC) of human abdominal aorta affected by atherosclerotic lesions (14) . In particular, all of the 84 surgical samples analyzed contained DNA adducts measured by 32P postlabeling; DNA adduct levels were significantly correlated with known atherogenetic risk factors including age, number of currently smoked cigarettes, arterial pressure, blood cholesterol (total/high density lipoproteins), triglycerides, and oxidative DNA damage in the same cells (14) . These conclusions were further supported by a study evaluating 30 thoracic aortic samples taken at autopsy, DNA adduct levels being significantly correlated with total and low density lipoproteins cholesterol and higher in subjects with frequent atherosclerotic changes as compared to subjects with rare lesions (15) .

In the present study we evaluated the polymorphic status for GSTM1 and GSTT1 in the population of atherosclerotic patients who had previously been investigated for the presence of adducts to SMC DNA (14) . Aorta SMC DNA was tested due to the circumstance that small DNA aliquots were archived from our previous experiments (14) . Obviously, identical results would have been generated by analyzing the genotypes in other cells, such as white blood cells or hair bulb cells, whose collection does not require invasive techniques. Evidence is provided here that adduct levels in atherosclerotic lesions are significantly increased in individuals having the null GSTM1 genotype.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Atherosclerotic patients
A fragment of abdominal aorta affected by atherosclerotic lesions was removed at surgery for therapeutic purposes from atherosclerotic patients undergoing aortic graft due to severe aneurism or stenotic lesions of the subrenal aorta. Surgery was under the responsibility of Dr. G. L. Petrilli (Department of Vascular Surgery, Galliera Hospital, Genoa). For each patient, we collected information concerning several parameters including age, gender, and clinical and laboratory parameters. We refer to our previous paper (14) for details on the examined population, which in the present study included a total of 75 patients, 31 of whom were current smokers, 7 had never smoked (‘never-smokers’), and 37 were ex-smokers, who quit smoking at least 2 years before sample collection.

DNA extraction from aorta SMC
The aorta samples were immersed in cold sterile physiological saline solution, transported at low temperature to our laboratory, and immediately processed as described in detail (14) . The tunica media, mainly composed of SMC, was used for DNA extraction by using an automatic DNA extractor (Genepure 341, Applied Biosystems, Foster City, Calif.), as described previously (14) . Lyophilized DNA aliquots were shipped to the Epidemiology and Biomarker Branch, U.S. Environmental Protection Agency (Research Triangle Park, N.C.) where, under the responsibility of Drs. J. Lewtas and D. Walsh, 84 samples were analyzed by 32P postlabeling for the detection of DNA adducts; these data have been published (14) . Moreover, the samples from 39 subjects were analyzed for 8-hydroxy-2'-deoxyguanosine (8-OH-dG) levels by HPLC/ECD under the responsibility of Dr. P. Degan (National Institute for Cancer Research, Genoa, Italy), as reported previously (14) .

Genotyping analyses
Sufficient amounts of SMC DNA, stored at -80°C, were still available in our laboratory to perform 75 GSTM1 genotyping analyses and 68 GSTT1 genotyping analyses.

The GSTM1 polymorphic deletion genotype was determined as described by Zhong et al. (16) . The polymerase chain reaction (PCR) primers were P1 (5'-CGC.CAT.CTT.GTG.CTA.CAT.TGC.CCG-3'), P2 (5'-ATC.TTC.TCC.TCT.TCT.GTC.TC-3'), and P3 (5'-TTC.TGG.ATT.GTA.GCA.GAT.CA-3'). P1 and P3 amplify a 230 bp product specific for the GSTM1 gene. Moreover, P1 and P2 amplify a 157 bp product specific for the GSTM4 gene, which, never having been deleted, was used as an internal control. PCR reaction was carried out in a total volume of 100 µl containing 1 µg of DNA, 200 µM each of ATP, GTP, TTP, and CTP, 10 µl DMSO, 50 mM MgCl2, and 2 U of PlatinumR Taq DNA Polymerase (Life Technologies, Rockville, Md.) in PCR buffer. After 5 min at 94°C needed to activate the polymerase (hot start method), the reaction was subjected to 35 cycles of amplification at 94°C for 1 min, 52°C for 1 min, and 72°C for 1 min by using a thermal cycler (Gene CyclerTM, Bio-Rad, Hercules, Calif.). The PCR product (25 µl) was run on 2% agarose gel in TAE buffer (40 mM Tris acetate, 1 mM EDTA, pH 8.0). The gel was stained in ethidium bromide and photographed by UV transillumination.

The GSTT1 polymorphic deletion genotype was determined as described by To-Figueras et al. (17) . The PCR primers were P1 (5'-TTC.CTT.ACT.GGT.CCT.CAC.ATC.TC-3') and P2 (5'-TCA.CCG.GAT.CAT.GGC.CAG.CA-3'), which amplify a 480 bp product specific for the GSTT1 gene. GSTM4 gene amplification was used as an internal control. PCR reaction and gel electrophoresis were carried out as described for GSTM1.

Statistical analyses
DNA adduct levels and other continuous variables (age, body weight, mass index, number of cigarettes smoked per day, blood cholesterol and triglycerides, and 8-OH-dG in SMC DNA) were compared in individuals carrying the GSTM1 and/or GSTT1 genotype vs. individuals having null genotype(s) by nonparametric Mann-Whitney U test. Correlations between genotype polymorphisms and dichotomized variables (gender, atherosclerosis family history, diabetes, alcohol consumption, fat intake, and hypertension) were assessed by Fisher’s exact test and {chi}2 test.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
As described previously (14) , the autoradiographic patterns of 32P postlabeled DNA adducts had revealed the presence of up to 9 individual spots and of a diagonal radioactive zone (DRZ). Table 1 shows that, of a total of 75 atherosclerotic patients for whom SMC DNA was still available, 39 (52.0%) had a null GSTM1 genotype. Irrespective of smoking habits (all patients), DNA adduct levels detected by 32P postlabeling after digestion with nuclease P1 were consistently higher in subjects lacking the GSTM1 genotype (GSTM1-) than in subjects possessing this genotype (GSTM1+). Among all patients, these differences were statistically significant for total DNA adducts, DRZ, and spots 3, 5, 7, 8, and 9. Among smokers, total DNA adducts, DRZ, and all 9 spots were higher in GSTM1- subjects than in GSTM1+ subjects, with ratios up to 4.0, but none of these differences was statistically significant. The category grouping never-smokers and ex-smokers showed striking differences in DNA adduct levels as related to the GSTM1 genotype, with ratios of up to 7.2. These differences were significant for total DNA adducts, DRZ, and spots 3, 5, 7, 8, and 9.


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  		Table 1. Relationships between the GSTM1 genotype status and DNA adduct levels in SMC of atherosclerotic lesions affecting the abdominal aorta taken from patients undergoing surgery. DNA adducts were detected by 32P postlabeling after nuclease P1 enrichmenta

After enrichment of DNA adducts with butanol (Table 2 ), DNA adduct levels were generally higher in atherosclerotic patients with null GSTM1 genotype. However, the differences were less pronounced than after enrichment with nuclease P1, and reached the statistically significant threshold only for DRZ and spot 9 among all patients, and for spot 9 among never-smokers and ex-smokers.


View this table:
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  		Table 2. Relationships between the GSTM1 genotype status and DNA adduct levels in SMC of atherosclerotic lesions affecting the abdominal aorta taken from patients undergoing surgery. DNA adducts were detected by 32P postlabeling after butanol enrichmenta

Twenty-two of the 68 investigated patients (32.4%) had a null GSTT1 genotype. DNA adduct levels were not influenced by this polymorphism (data not shown). Only for spot 9, as detected after digestion with nuclease P1, the levels were remarkably but not significantly higher among all patients with null GSTT1 genotype (ratio = 3.1) and among never-smokers and ex-smokers (ratio = 3.4).

We then evaluated the combined effect of GSTM1 and GSTT1 genotypes as related to DNA adduct levels. Fifteen of 67 subjects in whom both genotypes were examined (22.4%) had a null genotype in both GSTM1 and GSTT1 loci. DNA adduct levels were significantly higher in smokers and ex-smokers lacking both genotypes just for spot 9 after nuclease P1 digestion (P=0.05) and spot 3 after butanol extraction (P<0.05).

Neither GSTM1 nor GSTT1 polymorphisms were associated with variables regarding the examined subjects such as age, gender, blood cholesterol and triglycerides, arterial pressure, body mass index, occurrence of diabetes, family history for atherosclerosis, alcohol consumption, fat intake, and number of cigarettes smoked per day.

The intensity of oxidative DNA damage, as evaluated by measuring the levels of 8-OH-dG in SMC DNA (14) , was higher in patients lacking the GSTM1 and/or GSTT1 genotypes. In fact, 8-OH-dG levels (means±SD) were 2.1-fold higher in all patients with null GSTM1 genotype (189.1±319.5 8-OH-dG/105 dG, n=18) compared with those carrying this genotype ( 88.6±208.9, n=18). They were 1.7-fold higher in patients with null GSTT1 genotype (220.1±383.1 8-OH-dG/105 dG, n=6) compared to those carrying this genotype (131.5±267.4, n=25). Finally, they were 2.5-fold higher in patients lacking both GSTM1 and GSTT1 genotypes (307.4±462.7 8-OH-dG/105 dG, n=4) vs. those carrying both genotypes (125.1±217.9, n=27). However, despite the trend toward higher levels in patients with null genotypes, the differences were not statistically significant, possibly because of the large interindividual variability in 8-OH-dG levels and the small number of patients with null GSTT1 genotype. Unfortunately, due to the small subsets of patients and the uneven distribution of both GSTM1 and GSTT1 genotypes, it was not possible to stratify 8-OH-dG data for smoking status.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Although no mechanistic inference can be established, the results obtained in the present study provide evidence for the first time that metabolic polymorphisms are associated with the extent of nucleotide alterations in SMC DNA obtained from aorta segments affected by atherosclerotic lesions. In turn, these DNA alterations have been shown to be significantly correlated with occurrence of atherogenic risk factors known from traditional epidemiology (14 , 15) . In particular, lack of the GSTM1 genotype was significantly associated with levels of total DNA adducts detected by 32P postlabeling after enrichment with nuclease P1, with the intensity of DRZ, which typically reflects exposures to the multiplicity of DNA binding agents present in complex mixtures, as well as with levels of individual spots that underlie nucleotide alterations due to individual agents or metabolites. No such associations could be established with lack of the GSTT1 genotype. Moreover, the effect produced by the GSTM1 null genotype was not reinforced, but rather weakened, by concomitant lack of the GSTT1 genotype.

Oxidative damage to SMC DNA evaluated in terms of 8-OH-dG levels (14) was more intense in atherosclerotic patients having null GSTM1 and/or GSTT1 genotype(s), but this effect was not statistically significant, also due to the striking interindividual variability regarding this end point within each group. Nevertheless, a possible role of the investigated polymorphisms on oxidative DNA damage is suggested by the fact that lack of GSTM1 and GSTT1 had the greatest influence on levels of spot 9, which had previously been reported to be highly correlated with oxidative DNA damage (14) . It should also be noted that nuclease P1 is more sensitive than butanol enrichment in detecting oxidative DNA lesions (18) , whereas these procedures have a comparable sensitivity for DNA adducts formed by metabolites of polycyclic aromatic hydrocarbons, and butanol is more efficient in enriching DNA adducts due to aromatic amines (19) .

The fact that DNA adduct levels in patients carrying the GSTM1 genotype were similar in current smokers and never-smokers or ex-smokers suggests that, in the examined subjects, these molecular lesions were originating mainly from exposures other than current smoking. Thus, the finding that the GSTM1 null genotype was mainly associated with significant increases of DNA alterations in never-smokers or ex-smokers as compared to current smokers is difficult to interpret, also in the light of gene–environment interactions. It is well known that metabolic susceptibility factors are widespread in the population but have a low penetrance (7) . In Caucasian populations, the GSTM1 locus has been found to be entirely deleted in 30–50% of individuals (20) , whereas the GSTT1 locus is deleted in 15–30% of individuals (21) . However, consistent variations of GSTT1 null prevalence have been reported among different Caucasian ethnic groups (22) . Thus, the prevalence of null GSTM1 and GSTT1 genotypes among the atherosclerotic patients examined in the present study was near the upper limits of the above ranges. Most likely, the massive exposure of current smokers to DNA binding agents may have overwhelmed the defense mechanisms provided by this phase II enzyme, which, conversely, were sufficient to protect SMC DNA in the examined never-smokers and ex-smokers. Indeed, DNA damage is affected by the interplay between polymorphic status and environmental exposures. It is also known that micronutrient levels play a role in DNA adduct formation in individuals with null GSTM1 genotype (23) . GST activity is not only genetically determined but can also be induced by exposure to foreign substances, which suggests that these enzymes form an adaptive system to chemical stress (24) .

Other types of genetic polymorphisms, unrelated to metabolism of xenobiotics, have been shown to affect the risk of developing atherosclerosis and other cardiovascular diseases (see, e.g., refs 25 26 27 28 29 ). Although allelic variations in the vitamin D receptor locus (VDR) were associated with the severity of coronary heart disease, no relation was found between GSTM1 and GSTT1 polymorphic status and DNA adduct levels in the heart of 41 surgery patients (30) . DNA adducts in perennial cardiac myocytes have tentatively been implicated in the pathogenesis of cardiomyopathies (31) . The different situation observed in human heart and aorta can be explained by taking into account that the selective effect of metabolic polymorphisms in different tissues is likely to reflect the extent of local production of the encoded enzymes. Thus, metabolism of xenobiotics is poor in the heart (31) and more intense in aorta SMC, which (as assessed in animal models) possess a complete set of enzymes that activate polycyclic aromatic hydrocarbons (reviewed in refs 31 , 32 ). GST isoforms provide a major cellular defense against electrophilic atherogens, also including atherogenic unsaturated aldehydes (33) . GST isoforms such as GST8–8, which is localized in rat aorta SMC, are induced in an experimental model using allylamine, an atherogenic alkylating agent (34) . By analogy, the controversial issue regarding the role of GSTM1 polymorphism in smoke-related lung cancer may be ascribed in part to the fact that GSTM1 expression in the lung is low or even undetectable (35) . In fact, the results of a meta-analysis of literature data indicates that lack of GSTM1 alone increases susceptibility to lung cancer among smokers just to a limited extent, with a relative risk of 1.4 (36) .

In interpreting the results, we should keep in mind that all analyzed tissue specimens were from areas affected by atherosclerotic lesions, and factors other than metabolizing enzymes, such as cell turnover, could have affected the adduct levels. It will be of interest to evaluate similar correlations in healthy tissue specimens. A clinical study found that lack of GST activity in whole blood was associated with intermittent claudication (37) , and a recent epidemiological study showed that smokers having null GSTM1 genotype have a consistently higher prevalence of coronary heart disease (38) . In contrast, another recent epidemiological study reported a significantly decreased risk of acute myocardial infarction in smoking patients having null GSTM1 genotype, but only in those having a previous history of the same disease (39) .

In conclusion, the results presented here provide evidence that metabolic polymorphisms, which are usually investigated as a biomarker of susceptibility to carcinogens, can also play a role in atherosclerosis by modulating DNA damage produced in arterial SMC by those genotoxic agents that can be detoxified via conjugation with GSH. In fact, DNA adducts provide a fingerprint of exposure and a biomarker of procarcinogenic (9) and proatherogenic (14 , 15) DNA damage. Thus, a relatively simple genotyping for GSTM1 polymorphism may provide a new tool for predicting the interindividual susceptibility to genotoxic atherogens.

This work was supported by a grant from the Associazione Italiana per la Ricerca sul Cancro. This paper has been reviewed in accordance with the U.S. Environmental Protection Agency’s peer and administrative review policies and approved for publication. Mention of trade names or commercial products does not constitute endorsement or recommendation for use.

Received for publication May 22, 2000. Revision received September 14, 2000.
   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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