Are glutathione S transferases involved in DNA damage signalling? Interactions with DNA damage and repair revealed from molecular epidemiology studies

Our plain-English summary of Are glutathione S transferases involved in DNA damage signalling? Interactions with DNA damage and repair revealed from molecular epidemiology studies, by M. Dusinska, M. Staruchova, A. Horska, et al (Mutation Research, 2012).

The study

• Authors: M. Dusinska, M. Staruchova, A. Horska, B. Smolkova, A. Collins, S. Bonassi, K. Volkovova
• Journal: Mutation Research
• Published: 2012;736(1-2):130-7
• Cited by: 60 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Glutathione S-transferases (GSTs) are members of a multigene family of isoenzymes that are important in the control of oxidative stress and in phase II metabolism. Acting non-enzymically, GSTs can modulate signalling pathways of cell proliferation, cell differentiation and apoptosis. Using a molecular epidemiology approach, we have investigated a potential involvement of GSTs in DNA damage processing, specifically the modulation of DNA repair in a group of 388 healthy adult volunteers; 239 with at least 5 years of occupational exposure to asbestos, stone wool or glass fibre, and 149 reference subjects. We measured DNA damage in lymphocytes using the comet assay (alkaline single cell gel electrophoresis): strand breaks (SBs) and alkali-labile sites, oxidised pyrimidines with endonuclease III, and oxidised purines with formamidopyrimidine DNA glycosylase. We also measured GST activity in erythrocytes, and the capacity for base excision repair (BER) in a lymphocyte extract. Polymorphisms in genes encoding three GST isoenzymes were determined, namely deletion of GSTM1 and GSTT1 and single nucleotide polymorphism Ile105Val in GSTP1. Consumption of vegetables and wine correlated negatively with DNA damage and modulated BER. GST activity correlated with oxidised bases and with BER capacity, and differed depending on polymorphisms in GSTP1, GSTT1 and GSTM1. A significantly lower BER rate was associated with the homozygous GSTT1 deletion in all asbestos site subjects and in the corresponding reference group. Multifactorial analysis revealed effects of sex and exposure in GSTP1 Ile/Val heterozygotes but not in Ile/Ile homozygotes. These variants affected also SBs levels, mainly by interactions of GSTP1 genotype with exposure, with sex, and with smoking habit; and by an interaction between sex and smoking. Our results show that GST polymorphisms and GST activity can apparently influence DNA stability and repair of oxidised bases, suggesting a potential new role for these proteins in DNA damage processing via DNA damage signalling.

Copyright © 2012 Elsevier B.V. All rights reserved.

In plain English

This Slovak molecular epidemiology study asked whether glutathione S-transferases (GSTs), detoxifying enzymes, are linked to DNA damage and repair. Of 388 healthy volunteers, 239 had at least 5 years of occupational exposure to asbestos (61), stone wool (98) or glass fibres (80); 149 were reference subjects. The authors measured DNA damage and repair in white blood cells, red-cell GST activity and three GST gene variants. In simple group comparisons, repair did not differ with exposure, except that asbestos-site reference women had higher repair activity than asbestos-exposed women. A multifactorial analysis, however, found effects of sex and exposure on repair rate among people with the GSTP1 Ile/Val genotype (P = 0.030). At the asbestos site, people lacking the GSTT1 gene had lower repair rates (99.0 versus 120.5 arbitrary units, P = 0.047). At all three sites, higher GST activity was associated with fewer oxidised DNA bases. The authors concluded that GST variants and activity can apparently influence DNA stability and repair, and proposed a possible role in DNA damage signalling. They cited confounding and small group sizes as limitations.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Molecular epidemiology (biomonitoring) study comparing exposed workers with reference subjects, using blood biomarkers
• Who was studied: 388 healthy adult volunteers, aged 21 to 88 (227 men, 161 women). They comprised 239 workers from 3 industrial areas in western and middle Slovakia (asbestos 61, stone wool 98, glass fibres 80) and 149 reference subjects matched by age, sex and smoking. Sampling took place in September to October 2000 and September 2001.
• Exposure: At least 5 years of occupational exposure to asbestos (fiber type not specified; the plant had formerly produced asbestos), stone wool or glass fibres. No exposure levels were given.
• Main results:
  • In the group comparisons (Table 1), DNA repair activity was not influenced by exposure. The only difference was that reference women at the asbestos site had higher repair (incision) activity than asbestos-exposed women.
  • In multifactorial analysis of repair rate, sex and exposure had significant effects in GSTP1 Ile/Val heterozygotes but not in Ile/Ile homozygotes (P = 0.030).
  • Women from reference groups with the GSTP1 Ile/Val genotype had significantly higher repair rates than exposed subjects with the same genotype (P = 0.016).
  • At the asbestos site, subjects with the GSTT1 deletion had a lower repair rate than those with the gene present. In all asbestos-site subjects this was 99.0 (n=22) versus 120.5 (n=107), P = 0.047. In the asbestos reference group it was 93.1 (n=15) versus 121.3 (n=55), P = 0.035 (arbitrary units).
  • At all three sites, GST activity correlated inversely with oxidised DNA bases. For example, among all asbestos-site subjects, GST activity and EndoIII-sensitive sites gave r = −0.240, P = 0.007, N = 124.
  • At the asbestos site, GST activity correlated negatively with repair capacity: all subjects r = −0.193, P = 0.028; exposed r = −0.520, P = 0.001; men r = −0.331, P = 0.004. At the glass fibre site the correlation was positive.
  • Across all three sites, people with the GSTP1 Ile/Ile genotype had higher GST activity than those with the other two genotypes: Ile/Ile 106.3 U/g Hb (n=184), Ile/Val 92.4 (n=160), Val/Val 76.6 (n=42), P = 0.001.
  • In multifactorial analysis, DNA strand breaks were influenced by interactions of GSTP1 genotype with exposure, sex and smoking, and by an interaction between sex and smoking (P = 0.003).
  • Of 15 significant correlations between wine or vegetable consumption and DNA damage, 13 were inverse and 2 (involving white wine) were positive.
  • Repair rate correlated negatively with vegetable consumption in the combined reference group, in all asbestos-site subjects, and in the asbestos-exposed group (r = −0.273, P = 0.036, N = 59).
  • Repair rate correlated positively with age (all subjects r = 0.104, P = 0.043, N = 375). The authors called this counter-intuitive.
• The authors' conclusion: The authors concluded that GST polymorphisms and GST activity can apparently influence DNA stability and the repair of oxidised bases. They suggested a potential new role for GSTs in DNA damage processing via DNA damage signalling.
• Limitations the authors state:
  • Population study design limitations, many confounding factors, and relatively low numbers of subjects per group.
  • Large numbers of subjects are needed for firm conclusions about gene–environment interactions.
  • A high measured repair rate may reflect induction by high damage from exposure, which makes repair findings hard to interpret.
  • A pooled analysis with other studies is needed to establish the true relationship between repair and age.

Topics

Medical terms in this study, explained in our Lexicon: Glutathione (GSH), Epidemiology, Oxidative Stress, Apoptosis, Occupational Exposure, Comet Assay, Habit.

Related studies

• Vitamin C levels in blood are influenced by polymorphisms in glutathione S-transferases — A. Horska, C. Mislanova, et al. (2011)
• Polymorphism of glutathione S-transferase M1 and lung cancer risk among African-Americans and Caucasians in Los Angeles County, California — S.J. London, A.K. Daly, et al. (1995)
• Glutathione S-transferase and N-acetyltransferase genotypes and asbestos-associated pulmonary disorders — A. Hirvonen, S.T. Saarikoski, et al. (1996)
• Genetic polymorphism for glutathione-S-transferase mu in asbestos cement workers — K. Jakobsson, A. Rannug, et al. (1994)
• Glutathione S-transferases GSTM1 and GSTT1 polymorphisms and asbestosis — A. Franko, M. Dodic-Fikfak, et al. (2007)
• Radiographic changes and lung function in relation to activity of the glutathione transferases theta and mu among asbestos cement workers — K. Jakobsson, A. Rannug, et al. (1995)

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