BACKGROUND AND OBJECTIVE: Many environmental and genetic factors influence the development of chemoresistance. The goal of this study was to characterize the genetic variation in the ABCB1, GSTM1, GSTT1 and GSTP1 genes, as well as the haplotype structure in the ABCB1 gene. METHODS: Variants in these genes were studied in 109 healthy controls and 93 breast cancer cases, both of Caucasian origin. The cases were analyzed in relation to TP53 mutation status and response to doxorubicin. Both single and multiple single nucleotide polymorphism analyses were performed. RESULTS: Chi-square analyses revealed a significant association between TP53 mutation status and both the GA genotype of ABCB1 exon 11 (Ser400Asn) and the GG genotype of GSTP1 (Ile105Val; P
The aim of this work was a comparative study of the effects of spring diseases cytogenetic years of tick-borne encephalitis in elderly and young age due to differences in genes of glutathione-S-transferase. Surveyed by routine cytogenetics 120 patients with tick-borne encephalitis residents North of Tomsk region. We have taken in the study persons aged 20-35 years (Group 1) and 65-85 years old (Group 2). Material for study (buccal epithelium) was taken from each subject 3-5 times: 1st-2nd day after hospitalization, in 1 week, 1, 3 and 6 months. Tick-borne encephalitis infection causes a significantly large changes in cytogenetic regimens using buccal epithelium in the elderly than in younger patients. Restoring cytogenetic norms observed in a group of young in 3 months after hospitalization, in the elderly - in 6 months. When comparing cytogenetic effects of encephalitis shows: the young patients tick-borne encephalitis level by routine cytogenetics abnormal cells was significantly higher in carriers of inactive forms of gene GSTM1 (0)/GSTT1 (0) than containing active homozygous variants of these genes. Such patterns have not been noted in a group of elderly patients.
Aging adults are a growing segment of the U.S. population and are likely to exhibit increased susceptibility to many environmental toxicants. However, there is little information on the susceptibility of the aged to toxicants. The toxicity of toluene has been well characterized in young adult rodents but there is little information in the aged. Three approaches were used: (1) pharmacokinetic (PK), (2) cardiac biomarkers, and (3) whole-animal physiology to assess whether aging increases susceptibility to toluene in the Brown Norway (BN) rat. Three life stages, young adult, middle aged, and aged (4, 12, and 24 mo, respectively), were administered toluene orally at doses of 0, 0.3, 0.65, or 1 g/kg and subjected to the following: terminated at 45 min or 4 h post dosing, and blood and brain toluene concentration were measured; terminated at 4 h post dosing, and biomarkers of cardiac function were measured; or monitor heart rate (HR), core temperature (Tc), and motor activity (MA) by radiotelemetry before and after dosing. Brain toluene concentration was significantly elevated in aged rats at 4 h after dosing with either 0.3 or 1 g/kg. Blood toluene concentrations were unaffected by age. There were various interactions between aging and toluene-induced effects on cardiac biomarkers. Most notably, toluene exposure led to reductions in mRNA markers for oxidative stress in aged but not younger animals. Toluene also produced a reduction in cardiac endothelin-1 in aged rats. Higher doses of toluene led to tachycardia, hypothermia, and a transient elevation in MA. Aged rats were less sensitive to the tachycardic effects of toluene but showed a prolonged hypothermic response. Elevated brain levels of toluene in aged rats may be attributed to their suppressed cardiovascular and respiratory responses. The expression of several cardiac biochemical markers of toluene exposure in the aged may also reflect differential susceptibility to this toxicant.
Tuberculosis (TB) is one of the most important concerns of public health. There is evidence suggesting that genetic status is responsible for predisposition to infectious diseases including TB. To determine genetic risk factors of TB development, the frequencies of polymorphisms of genes CYP1A1, CYP2D6, CYP2C9, CYP2C 19, GSTT1, GSTM1, NAT2, MDR1, and NRAMP1 in 73 TB patients and 352 healthy individuals were determined by allele-specific hybridization using microarray technology. The TB patients have shown a significant increase in the frequency of the null GSTT1 genotype (OR = 3.26, 95% CI = 1.91 - 5.55, p = = 0.000028) as well as the double null GSTT1/GSTM1 genotype (OR = 4.05, 95% CI = 2.14 -7.65, p = = 0.000034) compared to the group of healthy donors. It was shown that the NAT2*5/*5 genotype in combination with the "null" GSTT1 and the double "null" GSTT1/GSTM1 genotypes was observed significantly more often in the TB patients than in the control sample. Thus the examined GSTT1, GSTM1 and NAT2 gene polymorphisms may potentially alter the risk of TB development in ethnic Russians and are of interest for further research using larger cohorts of patients.
The crustacean hyperglycaemic hormones (cHHs) are multifunctional neuropeptides that play a central role in the physiology of crustaceans. A partial cDNA coding for cHH of the Norway lobster, Nephrops norvegicus, was cloned; this cDNA was fused to glutathione- S-transferase (GST) to obtain a recombinant fusion protein that was used to raise a rabbit antiserum and to perform a biological assay. The specificity of the purified antibody was demonstrated by means of Western blotting. To validate the specificity of the purified antibody to the cHH of N. norvegicus and its cross-reactivity with other species, we performed standard immunocytochemistry of the eyestalk on: (1) paraffin sections of the decapod species N. norvegicus, Munida rugosa and Astacus leptodactylus and of the stomatopod Squilla mantis; (2) semithin resin sections of N. norvegicus and Palaemon elegans; (3) ultrathin sections of N. norvegicus sinus gland (transmission electron microscopy studies). The pattern of immunoreactivity shown by N. norvegicus eyestalk sections conforms to distribution, relative amount and ultrastructural features of cHH-containing neurons and nerve endings as reported in the previous literature. In all the crustacean species examined, the antibody marks precisely the X organ-sinus gland complex and unspecific staining is completely lacking. In addition, its specific cross-reaction by immunoprecipitation depletes shrimp eyestalk extract of hyperglycaemic activity in an in vivo bioassay. The results obtained show a cHH-specific molecular recognition despite the fact that the species tested belong to systematic groups increasingly remote in the phylogenetic tree. The antibody could be used for advancing our knowledge on cHH activity in a variety of crustacean species, e.g. for monitoring reproductive and stress conditions.
BACKGROUND: Glutathione transferases (GST) detoxify environmental and endogenous compounds and levels of two polymorphic GST proteins, GSTM3 and GSTP1, are high in the brain. Previous studies of GSTM3 and GSTP1 polymorphisms and adult brain tumor risk have produced inconsistent results, whereas the GSTM3 -63 variant is newly identified and, therefore, has not yet been studied in this context. We therefore examined associations between GSTM3 -63, GSTM3 *A/*B, GSTP1 105, and GSTP1 114 variants and adult brain tumor risk and the interaction of the effects of these same polymorphisms with cigarette smoking. In addition, the enzymes NQO1 and CYP1A1 alter susceptibility to oxidative brain damage. Because there is less previous evidence for a role of NQO1, CYP1A1, GSTM1, and GSTT1 variants, we restricted analysis of these variants to a small preliminary study. METHODS: We genotyped DNA collected for an international population-based case-control study of 725 glioma cases, 329 of which were glioblastoma cases, 546 meningioma cases and 1,612 controls. Study participants were residents of Sweden, southeast England, Denmark, and Finland. RESULTS: We found no associations between the GSTM3, GSTP1, NQO1, CYP1A1, GSTM1, or GSTT1 polymorphisms and adult brain tumor risk with the possible exception of a weak association between the G-C (Val-Ala) GSTP1 105/114 haplotype and glioma [odds ratio (OR), 0.73; 95% confidence interval (95% CI), 0.54, 0.99], nor was there an interaction between the effects of the GSTM3 or GSTP1 polymorphisms and cigarette smoking. CONCLUSIONS: Overall, we observed no strong evidence for an association between GST or related enzyme polymorphisms and adult brain tumor risk.
Plasma autoantibodies (aAbs) against the oxidized DNA base derivative 5-hydroxymethyl-2'-deoxyuridine (5-HMdU) are potential biomarkers of cancer risk and oxidative stress. We examined their association with a number of cancer risk factors: smoking, alcohol habits, body fatness, and absence of the glutathione S-transferases M1 and T1 (GSTM1 and GSTT1) in a sample from the population-based Malmö Diet and Cancer cohort (Sweden). This was a cross-sectional study of 264 men and 280 women, 46-67 years of age. Anti-5-HMdU aAb concentration was determined by an ELISA. Data on tobacco exposure were collected through a questionnaire. Alcohol consumption was estimated by a modified diet history method. Body fatness was assessed by a bioimpedance method. The absence or presence of genes coding for GSTM1 and GSTT1 was determined in granulocyte DNA by a multiplex PCR technique. aAb titers were significantly greater in those with high alcohol consumption. Current smokers lacking GSTM1, particularly men, had greater aAb titers compared with nonsmokers or persons expressing GSTM1. Body fatness was inversely associated with antibody titers in men. GSTT1 genotype was not associated with aAb titers. Overall, women had higher aAb titers than men. Adjustment for potential confounders (history of chronic diseases, anti-inflammatory medication, and season of blood sampling) did not change the results. Our study shows that a high alcohol consumption, smoking in combination with lack of GSTM1, and low body fatness (in men) is associated with high titers of anti-5-HMdU aAbs in this population.
BACKGROUND: The frequency of chromosomal aberrations (CA) in peripheral blood lymphocytes of healthy individuals has been associated with cancer risk. It is presently unclear whether this association is influenced by individual susceptibility factors such as genetic polymorphisms of xenobiotic-metabolizing enzymes. OBJECTIVES: To evaluate the role of polymorphisms in glutathione S-transferase (GST) M1 (GSTM1) and theta 1 (GSTT1) as effect modifiers of the association between CA and cancer risk. METHODS: A case-control study was performed pooling data from cytogenetic studies carried out in 1974-1995 in three laboratories in Italy, Norway, and Denmark. A total of 107 cancer cases were retrieved from national registries and matched to 291 controls. The subjects were classified as low, medium, and high by tertile of CA frequency. The data were analyzed by setting up a Bayesian model that included prior information about cancer risk by CA frequency. RESULTS: The association between CA frequency and cancer risk was confirmed [OR(medium) (odds ratio)(medium) = 1.5, 95% credibility interval (CrI), 0.9-2.5; OR(high) = 2.8, 95% CrI, 1.6-4.6], whereas no effect of the genetic polymorphism was observed. A much stronger association was seen in the Italian subset (OR(high)= 9.4, 95% CrI, 2.6-28.0), which was characterized by a lower technical variability of the cytogenetic analysis. CA level was particularly associated with cancer of the respiratory tract (OR(high)= 6.2, 95% CrI, 1.5-20.0), the genitourinary tract (OR(high) = 4.0, 95% CrI, 1.4-10.0), and the digestive tract (OR(high) = 2.8, 95% CrI, 1.2-5.8). CONCLUSIONS: Despite the small size of the study groups, our results substantiate the cancer risk predictivity of CA frequency, ruling against a strong modifying effect of GSTM1 and GSTT1 polymorphisms.
Comment In: Environ Health Perspect. 2009 Jul;117(7):A286-7; author reply A287-819654892
Polymorphisms of glutathione S-transferase (GST) genes in mothers may be involved in teratogenesis in their offspring. This study aims to investigate the association of GST genes (T1, M1 and P1) with the risk of having children with congenital malformations (CMs) in residents of the West Siberian region of Russia.
We studied 235 women with offspring's with CMs, and 273 women with one or more healthy children. Null genotypes of GSTM1 and GSTT1 were identified through multiplex real-time polymerase chain reaction, and GSTP1 gene (Ile105Val) polymorphism was determined through TaqMan-real-time polymerase chain reaction.
The study showed that the maternal genotype GSTT1 «0/0» is associated with CMs in the offspring (odd ratio (OR)?=?3.63, P?=?5.18?×?10(-9) ). A significant association of the maternal genotype GSTT1 «0/0» with CMs of the cardiovascular system (OR?=?5.03, P?=?2.93?×?10(-7) ), urinary system (OR?=?4.20, P?=?3.51?×?10(-6) ) and central nervous system (OR?=?4.40, P?=?6.69?×?10(-5) ) was found in the child. No association of maternal GSTM1 (del) and GSTP1 (Ile105Val) genetic polymorphisms with CMs of the child was identified.
Homozygous deletion of the GSTT1 gene in women of the West Siberian region is a risk factor for birth defects in the child.
Polymorphism ofglutathione-S-transferase (GSTA1, GSTM1, GSTM3, GSTP1, and GSTT1) and DNA repair (ERCC1, ERCC2, and XRCC1) genes in samples of ovarian cancer patients and healthy women of the Russian ethnic group was studied. A trend in the allele frequency variation of ERCC2 gene single nucleotide polymorphism (rs13181, A > C) was revealed. The A allele frequency was higher in the sample of patients (60,6% versus 52,9%, P = 0.058).