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1.
The association between glutathione S-transferase M1 genotype and polycyclic aromatic hydrocarbon-DNA adducts in breast tissue. 总被引:3,自引:0,他引:3
A Rundle D Tang J Zhou S Cho F Perera 《Cancer epidemiology, biomarkers & prevention》2000,9(10):1079-1085
A major goal in molecular epidemiology is to identify preventable environmental risk factors and susceptible subpopulations. In a hospital-based molecular epidemiological case-control study of breast cancer, we investigated the relationship between DNA damage from exposure to polycyclic aromatic hydrocarbons (PAHs) and susceptibility attributable to inherited deletion of the xenobiotic detoxifying gene, glutathione S-transferase M1 (GSTM1). Prior to breast surgery, women (n = 227) were enrolled and interviewed and donated a blood sample. PAH-DNA adduct levels were measured by immunohistochemistry in breast tissue samples retrieved from pathology blocks, and GSTM1 genotype was determined by PCR using WBC DNA. The GSTM1 analysis included 95 cases and 87 benign breast disease controls. GSTM1 genotype was not associated with breast cancer case-control status (odds ratio = 0.73; 95% confidence interval, 0.37-1.44). However, the GSTM1 null genotype predicted PAH-DNA adduct levels in malignant (beta = 0.407; P = 0.003) and nonmalignant (beta = 0.243; P = 0.05) breast tissue from cases. This relationship was not seen in tissue from controls (beta = 0.095; P = 0.341). When tissue from controls was compared with tumor tissue from cases, there was a significant case-control difference in PAH-DNA adduct levels among women who were GSTM1 null. There was no such case-control difference among women who were homozygous or heterozygous for GSTM1. There was an interaction between GSTM1 and case-control status on adduct levels in breast tissue (P = 0.002). The results suggest that genetic susceptibility to the formation of PAH-DNA adducts in breast tissue may play a role in breast cancer development. 相似文献
2.
Detection of polycyclic aromatic hydrocarbon-DNA adducts in white blood cells of foundry workers 总被引:4,自引:0,他引:4
F P Perera K Hemminki T L Young D Brenner G Kelly R M Santella 《Cancer research》1988,48(8):2288-2291
Iron foundry workers, exposed to high levels of polycyclic aromatic hydrocarbons (PAHs), silica, and metal fumes and dusts, are at elevated risk of lung cancer. Benzo(a)pyrene and a number of structurally related PAHs are metabolically activated to diol epoxides (e.g., 7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a) pyrene) which are mutagenic, carcinogenic in experimental animals, and form covalent adducts with DNA. The levels of these adducts were measured in an enzyme-linked immunosorbent assay using a polyclonal anti-benzo(a)pyrene diol epoxide-I-DNA antibody which cross-reacts with DNA modified by diol epoxides of structurally related PAHs. DNA was analyzed from peripheral blood cells of 35 Finnish foundry workers and 10 controls. Workers were classified as having low (less than 0.05 micrograms/m3), medium (0.05-0.2 micrograms/m3), or high (greater than 0.2 micrograms/m3) exposure to benzo(a)pyrene (as an indicator of PAH). When adjustment was made for cigarette smoking and time since vacation, benzo(a)pyrene exposure was significantly related to adduct levels (P = 0.0001). Each of the three exposure groups had significantly elevated adduct levels compared to controls. Among the exposed workers, the low group differed significantly from the high and medium categories. This study supports the usefulness of monitoring adduct formation in a population occupationally exposed to carcinogens. 相似文献
3.
4.
Formation of polycyclic aromatic hydrocarbon-DNA adducts in peripheral white blood cells during consumption of charcoal-broiled beef 总被引:2,自引:1,他引:1
N Rothman M C Poirier M E Baser J A Hansen C Gentile E D Bowman P T Strickland 《Carcinogenesis》1990,11(7):1241-1243
The effect of ingesting charcoal-broiled (CB) beef on polycyclic aromatic hydrocarbon (PAH)-DNA adduct levels in nucleated peripheral white blood cells (WBCs) was examined in four healthy, non-smoking males who consumed an average of 280 g CB beef daily for 7 days. PAH-DNA adducts were quantitated by enzyme-linked immunosorbent assay. During the week of CB beef consumption, two individuals exhibited a 3- to 6-fold increase in PAH-DNA adducts above baseline levels observed during the month prior to CB beef consumption. In contrast, PAH-DNA adduct levels in the two other subjects did not increase. Thus, dietary sources of PAH can contribute to the PAH-DNA adduct load in peripheral WBCs in some individuals. 相似文献
5.
Nathaniel Rothman Peter G. Shields Miriam C. Poirier Anita M. Harrington D. Patrick Ford Paul T. Strickland 《Molecular carcinogenesis》1995,14(1):63-68
Carcinogenic polycyclic aromatic hydrocarbons(a) form DNA adducts via a complex metabolic activation pathway that includes cytochrome P450(a) 1A1, whereas intermediate metabolites can be detoxified by conjugation through pathways including glutathione s-transferase M1 (GSTM1). PAH-DNA adducts can be measured in peripheral white blood cells (a) and should reflect the net effect of competing activation and detoxification pathways and ONA repair as well as exposure. We have previously shown that WBC PAH-DNA adducts measured by an enzyme-linked immunosorbent assay (a) were associated with recent, frequent consumption of charbroiled food among 47 nonsmoking wildland fire-fighters who provided two blood samples 8 wk apart. In the investigation reported here, which was performed in the same population, we measured the association between the GSTM1 null genotype, which results in loss of enzyme activity, and PAH-DNA adduct levels, hypothesizing that subjects with this genotype would have higher levels of DNA adducts because of their decreased ability to detoxify PAH metabolites. However, PAH-DNA adduct levels were nonsignificantly lower in subjects with the GSTM1 null genotype (n = 28) compared with other subjects (n=19) (median 0.04 fmol/μg DNA vs 0.07 fmol/μg DNA, respectively, P = 0.45, Wilcoxon rank-sum test). Adduct levels were also lower in the nine subjects heterozygous or homozygous for the CYP1A1 exon 7 polymorphism (which codes for a valine rather than isoleucine and is thought to be associated with greater CYP1A1 activity) compared with the 38 wild-type subjects (P = 0.12). In the entire group, there was a positive association between consuming charbroiled food and PAH-DNA adduct formation (r = 0.24, P = 0.02, Spearman rank-order correlation). This association was weaker in the subgroup of subjects with the GSTM1 null genotype (r = 0.03, P = 0.84) and stronger among the remaining subjects (r = 0.57, P = 0.0002). These results suggest that the GSTM1 null genotype and CYPT1A1 exon 7 polymorphism are not associated with increased susceptibility for PAH-DNA adduct formation in peripheral WBCs measured by ELISA in nonsmoking populations.© 1995 Wiley-Liss, Inc 相似文献
6.
7.
R M Whyatt W Jedrychowski K Hemminki R M Santella W Y Tsai K Yang F P Perera 《Cancer epidemiology, biomarkers & prevention》2001,10(6):581-588
Human and experimental evidence indicates that the developing fetus may be more susceptible than the adult to the effects of certain carcinogens, including some polycyclic aromatic hydrocarbons (PAHs). Factors that can modulate susceptibility include proliferation rates, detoxification capabilities, and DNA repair capacity. Biomarkers can facilitate quantification of age-related susceptibility among human populations. In this study, we report on three biomarkers measured in paired blood samples collected at birth from 160 Polish mothers and newborns: 70 pairs from Krakow (a city with high air pollution including PAHs) and 90 pairs from Limanowa (an area with lower ambient pollution but greater indoor coal use). Biomarkers were: WBC aromatic-DNA adducts by (32)P-postlabeling and PAH-DNA adducts by ELISA (as indicators of DNA damage from PAHs and other aromatics) and plasma cotinine (as an internal dosimeter of cigarette smoke). Correlations were assessed by Spearman's rank test, and differences in biomarker levels were assessed by the Wilcoxon signed-ranks test. A significant correlation between paired newborn/maternal samples was seen for aromatic-DNA adduct levels (r = 0.3; P < 0.001) and plasma cotinine (r = 0.8; P < 0.001) but not PAH-DNA adduct levels (r = 0.14; P = 0.13). Among the total cohort, levels of the three biomarkers were higher in newborn samples compared with paired maternal samples. The difference was significant for aromatic-DNA adduct levels (16.6 +/- 12.5 versus 14.21 +/- 15.4/10(8) nucleotides; P = 0.002) and plasma cotinine (14.2 +/- 35.5 versus 8.3 +/- 24.5 ng/ml; P < 0.001) but not for PAH-DNA adduct levels (7.9 +/- 9.9 versus 5.9 +/- 8.2/10(8) nucleotides; P = 0.13). When analyses were restricted to the 80 mother/newborn pairs from whom the blood sample was drawn concurrently (within 1 h of each other), levels of all of the three biomarkers were significantly higher in the newborn compared with paired maternal blood samples (P < 0.05). Results suggest reduced detoxification capabilities and increased susceptibility of the fetus to DNA damage, especially in light of experimental evidence that transplacental exposures to PAHs are 10-fold lower than paired maternal exposures. The results have implications for risk assessment, which currently does not adequately account for sensitive subsets of the population. 相似文献
8.
Kang D.H.; Rothman N.; Poirier M.C.; Greenberg A.; Hsu C.H.; Schwartz B.S.; Baser M.E.; Groopman J.D.; Weston A.; Strickland P.T. 《Carcinogenesis》1995,16(5):1079-1085
Biological markers of internal dose and macromolecular dosefrom PAHs provide a potential means of assessing environmentalexposure to PAHs through inhalation, ingestion and percutaneousabsorption. In this study we examined the time course and interindividualvariation of 1-hydroxypyrene-glucuronide (1-OHP-gluc) excretionin urine and PAHDNA adduct formation in peripheral whiteblood cells (WBCs) after charbroiled (CB) beef consumption.As a marker of internal dose, 1-OHP-gluc was measured in humanurine using immunoaffinity chromatography and synchronous fluorescencespectroscopy. PAHDNA adducts were measured in WBCs byenzyme-linked immunosorbent assay (ELISA) in order to assessmacromolecular dose. Ten healthy non smoking males consumedidentical amounts of CB beef on five consecutive days. Multipleblood and urine samples were collected before, during, and afterthe feeding period. The morning after the first day of CB beefconsumption, individual urinary concentrations of 1-OHP-glucincreased 10- to 80-fold (range:2.016.6 pmol/ml urine)aboveprefeed baseline concentreations (0.23±0.11pmol/ml) inthe 10 subjects. 1-OHP-gluc concentration decreased to nearbaseline levels by 2472 h after CB beef consumption ended.In contrast, PAHDNA adducts in WBCs increased markedlyin only four of 10 subjects during or after CB beef consumption.Significant interindividual variation was observed for bothurinary 1-OHP-gluc concentration (P < 0.001 by KruskalWallis)and PAHDNA adduct levels (P < 0.005) during the feedingperiod. The mean urinary 1-OHP-gluc concentration for each subjectduring and immediately after (days 28) the feeding periodwas significantly correlated with their mean PAHDNA adductlevel in WBCs during the same time period (Spearman r = 0.79,P<0.01). Evidence of segregation of the subjects into separateresponse groups based on level of urinary 1-OHP-gluc was observed,suggesting that discrete determaints may regulate the absorption,metabolism and/or excretion of ingested pyrene. 相似文献
9.
Cigarette smoking related polycyclic aromatic hydrocarbon-DNA adducts in peripheral mononuclear cells. 总被引:2,自引:0,他引:2
R M Santella R A Grinberg-Funes T L Young C Dickey V N Singh L W Wang F P Perera 《Carcinogenesis》1992,13(11):2041-2045
Studies on cigarette smoking related polycyclic aromatic hydrocarbon-DNA adducts in blood have produced conflicting results. To determine whether a subset of specific white blood cells is a useful marker for monitoring exposure to cigarette smoke, blood was obtained from 63 heavy smokers and 27 non-smokers. Adduct levels were determined by competitive enzyme-linked immunosorbent assay with a polyclonal antiserum recognizing benzo[a]pyrene and structurally related diolepoxide-DNA adducts. Analysis of the lymphocyte plus monocyte fraction from smokers indicated 70% had detectable adducts with a mean of 4.38 +/- 4.29 adducts/10(8) nucleotides, while in non-smokers the corresponding values were 22% and 1.35 +/- 0.78/10(8) (P < 0.001). Plasma cotinine levels differed significantly in smokers (286 +/- 90 micrograms/l) compared to non-smokers (4.4 +/- 3.3 micrograms/l) (P < 0.001). However, cotinine was not correlated with self-reported smoking history in these heavy smokers. Nor were DNA adducts in smokers correlated with cigarettes per day, pack-years and plasma cotinine, indicating large interindividual variation in DNA adduct formation. These data demonstrate lymphocytes plus monocytes from smokers have elevated levels of polycyclic aromatic hydrocarbon diolepoxide-DNA adduct levels compared to non-smokers. 相似文献
10.
Shunji Morita Masahiko Yano Toshimasa Tsujinaka Atsuhiro Ogawa Masaaki Taniguchi Katsuhiko Kaneko Hitoshi Shiozaki Yuichiro Doki Masatoshi Inoue Morito Monden 《International journal of cancer. Journal international du cancer》1998,79(5):517-520
We examined the effect of genetic polymorphisms of phase-II enzymes, glutathione S-transferase P1 (GSTP1) and N-acetyltransferase2 (NAT2) on susceptibility to esophageal squamous-cell carcinoma. To determine the genotypes of the 2 polymorphisms, PCR-based analysis was performed on samples from 66 Japanese patients who had been histologically diagnosed as having esophageal squamous-cell carcinoma, and 164 healthy Japanese controls. The frequency of the AA genotype of GSTP1 was significantly higher in esophageal-cancer patients than in the controls according to logistic-regression analysis (92% of the patients and 68% of the controls; odds ratio (OR), 8.0; p = 0.0013). Also, more patients had the slow and intermediate acetylator genotypes of NAT2 than the controls (15% and 38% vs. 10% and 32% respectively; OR of the slow acetylator genotype, 4.2; p = 0.032; OR of the slow plus intermediate acetylator genotypes, 2.9; p = 0.015). Polymorphisms of GSTP1 and NAT2 may serve as genetic biomarkers for predicting susceptibility to esophageal squamous-cell carcinoma. Int. J. Cancer (Pred. Oncol.) 79:517–520, 1998.© 1998 Wiley-Liss, Inc. 相似文献
11.
Wang Y Spitz MR Schabath MB Ali-Osman F Mata H Wu X 《Lung cancer (Amsterdam, Netherlands)》2003,40(1):25-32
Glutathione transferases (GSTs), a multiple gene family of phase II enzymes, catalyze detoxifying endogenous reactions with glutathione and protect cellular macromolecules from damage caused by cytotoxic and carcinogenic agents. Glutathione S-transferase p1 (GSTP1), the most abundant GST isoform in the lung, metabolizes numerous carcinogenic compounds including benzo[a]pyrene, a tobacco carcinogen. Previous studies suggest that genetic polymorphisms of GSTP1 exon 5 (Ile105Val) and exon 6 (Ala114Val) have functional effects on the GST gene product resulting in reduced enzyme activity. Individuals with reduced GST enzymatic activity may be at a greater risk for cancer due to decreased detoxification of carcinogenic and mutagenic compounds. Utilizing a hospital-based case-control study, we investigated the association between GSTP1 polymorphisms at exons 5 and 6 with lung cancer risk. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was used to successfully genotype the GSTP1 exons 5 and 6 polymorphism in 582 Caucasian lung cancer cases and 600 frequency matched Caucasian controls. There was no association between the exon 5 variant genotypes (A/G+G/G) and overall lung cancer risk (OR=1.09; 95% CI 0.82-1.45) nor when stratified by age, gender, and smoking status. However, the exon 6 variant genotypes (C/T+T/T) were associated with a statistically significant elevated lung cancer risk (OR=1.40; 95% CI 1.06-1.92). Additionally, there was an increase in lung cancer risk for the exon 6 variant genotypes in younger individuals (<62 years) (OR=1.63; 95% C.I. 1.07-2.49) but no effect in older individuals (OR=1.14; 95% CI 0.72-1.81). A statistically significant increased risk of lung cancer was also observed for the exon 6 variant genotypes among men (OR=2.17; 95% CI 1.41-3.33), but not among women (OR=0.80; 95% CI 0.51-1.28). Among ever smokers, the exon 6 variant genotypes were associated with an elevated lung cancer risk (OR=1.58; 95% CI 1.14-2.19), which was not evident for never smokers (OR=0.53; 95% CI 0.21-1.33). These data demonstrate that the GSTP1 exon 6 polymorphism, but not the exon 5 polymorphism, is associated with lung cancer risk that is especially evident in men, younger individuals, and ever smokers. 相似文献
12.
Modulation of benzo[a]pyrene diolepoxide-DNA adduct levels in human white blood cells by CYP1A1, GSTM1 and GSTT1 polymorphism 总被引:7,自引:0,他引:7
Rojas M Cascorbi I Alexandrov K Kriek E Auburtin G Mayer L Kopp-Schneider A Roots I Bartsch H 《Carcinogenesis》2000,21(1):35-41
The modulation of benzo[a]pyrene diolepoxide (BPDE)-DNA adduct levels by polymorphisms in the CYP1A1, GSTM1 and GSTT1 genes was assessed in leukocytes of Caucasian males. Eighty-nine coke oven workers (35 smokers, 36 ex-smokers and 18 non-smokers) were recruited from job categories with different exposure levels to polycyclic aromatic hydrocarbons (PAH), together with 44 power plant workers (all smokers) not exposed to PAH. BPDE-DNA adducts were detected in 69 of 133 (52%) DNA samples with a 100-fold variation (range 0.2-44 adducts/10(8) nt) and a median of 1.6 adducts/10(8) nt. All samples with the GSTM1 active genotype (n = 59) and five out of 74 samples with GSTM1*0/*0 (7%) showed non-detectable adducts (<0.2 adducts/10(8) nt) and 69 of 74 subjects with GSTM1*0/*0 (93%) had detectable adducts (>0.2 adducts/10(8) nt). The difference in adduct level between the GSTM1*0/*0 and GSTM1 active genotypes was highly significant (P < 0.0001). No significant difference in adduct level between the GSTT1*0/*0 and GSTT1 active genotypes was seen. All heterozygotes (CYP1A1*1/*2) from subjects of GSTM1 active type did not have detectable adducts. Among the GSTM1-deficient individuals (n = 69), 42 with the CYP1A1*1/*1 genotype showed a lower adduct level (median 1.3, range 0.2-4.1 adducts/10(8) nt) compared with 26 individuals with heterozygous mutated CYP1A1*1/*2 genotypes (median 2.5, range 0.4-6.1 adducts/10(8) nt, P < 0.015). One individual with low PAH exposure and the rare combination CYP1A1*2A/*2A-GSTM1*0/*0 showed an extremely high level of 44 adducts/10(8) nt. Significant differences in detectable adduct levels were found between the CYP1A1*1/*1 and CYP1A1*1/*2 genotypes in the exposed group low + medium (P = 0.01) and for all adduct levels, detectable and non-detectable (set at a fixed value), in highly exposed individuals and in ex-smokers (P = 0.03), whereas no such differences were observed in the control group. Mutated CYP1A1*1/*2 increased the adduct level in non-smokers from the exposed group (1.4 versus 2.2 adducts/10(8) nt), but had no effect on the smokers from the exposed group (2.3 versus 2.8 adducts/10(8) nt). When all variables were dichotomized, statistical evaluation showed that CYP1A1 status (P = 0.015), PAH exposure (P = 0.003) and smoking (P = 0.006) had significant effects on adduct levels which increased in the order: CYP1A1*1/*1 < CYP1A1(*1/*2 or *2A/*2A); environmental exposure < occupational exposure; non-smokers < smokers, whereby adducts increased with cigarette dose and the duration of smoking. Higher levels of BPDE-DNA adducts in individuals with the combined CYP1A1(1/*2 or *2A/*2A)-GSTM1*0/*0 genotype suggest that these genotype combinations are at increased risk for contracting lung cancer when exposed to PAH. 相似文献
13.
Polycyclic aromatic hydrocarbon-DNA adducts in human placenta and modulation by CYP1A1 induction and genotype 总被引:6,自引:1,他引:5
Whyatt RM; Bell DA; Jedrychowski W; Santella RM; Garte SJ; Cosma G; Manchester DK; Young TL; Cooper TB; Ottman R; Perera FP 《Carcinogenesis》1998,19(8):1389-1392
This study investigated the relationship in human placenta between
polycyclic aromatic hydrocabon (PAH)-DNA adduct levels and two biomarkers
of cytochrome P4501A1 (CYP1A1): gene induction evidenced by CYP1A1 mRNA,
and a genetic polymorphism, the CYP1A1 MspI RFLP. CYP1A1 codes for an
inducible enzyme system that catalyzes the bioactivation of PAHs. Prior
research found a high correlation in human lung tissue between CYP1A1
activity and DNA damage from PAHs. The CYP1A1 Mspi RFLP has been linked in
some studies to risk of lung cancer. The relationships in human placenta
between DNA damage, CYP1A1 activity and genotype have not been well
characterized and may be relevant to risks from transplacental PAH
exposure. The study cohort consisted of 70 newborns from Krakow, Poland, a
city with elevated air pollution, and 90 newborns from nearby Limanowa, an
area with lower air pollution but greater indoor coal use. Contrary to
results seen previously in lung tissue, CYP1A1 mRNA was not significantly
correlated with PAH-DNA adduct levels in the placenta. Smoking
(self-reported maternal and infant plasma cotinine) was significantly
associated with CYP1A1 mRNA levels (P < 0.01), but not with PAH-DNA
adduct levels. Placental PAH- DNA adduct levels were significantly higher
in infants with the CYP1A1 MspI restriction site compared with infants
without the restriction site (P < 0.01), implicating a genetic factor in
inter-individual variation in DNA damage in human placenta. Further studies
are needed to determine the relevance of this finding to risk of
transplacental carcinogenesis.
相似文献
14.
Biological monitoring of fire fighters: sister chromatid exchange and polycyclic aromatic hydrocarbon-DNA adducts in peripheral blood cells 总被引:1,自引:0,他引:1
S H Liou D Jacobson-Kram M C Poirier D Nguyen P T Strickland M S Tockman 《Cancer research》1989,49(17):4929-4935
Fire fighters are exposed to potentially carcinogenic combustion and pyrolysis products during the course of their work. The present study was designed to test 43 fire fighters and matched controls for DNA damage which might be related to occupational carcinogen exposures. Using peripheral blood lymphocytes, we examined (a) baseline sister chromatid exchange (SCE) frequency and (b) SCE induction by in vitro mutagenic challenge with mitomycin C. Using nucleated peripheral blood cells, we examined (c) polycyclic aromatic hydrocarbon-DNA adduct levels by assessing benzo(a)pyrene diol epoxide (BPDE)-DNA antigenicity. Exposures were determined from histories of fire-fighting activity. The presence of confounding factors (e.g., tobacco smoking, charcoal-broiled food consumption, etc.) was determined by questionnaire. Plasma cotinine levels were measured to assess recent exposures to tobacco smoke. White fire fighters exhibited a significantly higher risk for the presence of detectable BPDE-DNA antigenicity than white controls (odds ratio, 3.4; 95% confidence interval, 1.08-10.5 after adjustment). Consumption of charcoal-broiled food less than 3 times a month was associated with a smaller proportion of individuals exhibiting measurable (positive) BPDE-DNA antigenicity, while consumption of broiled food greater than 3 times a month did not affect the proportion of positive individuals. Daily alcohol consumption was associated with a larger proportion of individuals exhibiting positive BPDE-DNA antigenicity, (P = 0.07). Tobacco smoking and charcoal-broiled food consumption, but not fire fighting, were associated with increased levels of baseline SCE. Sensitivity to SCE induced by mitomycin C in cultured peripheral lymphocytes was similar in fire fighter and control groups. However, sensitivity of individual fire fighters to mitomycin C-induced SCE was correlated with number of fires fought in the previous 24 h. 相似文献
15.
G B Smith P A Harper J M Wong M S Lam K R Reid D Petsikas T E Massey 《Cancer epidemiology, biomarkers & prevention》2001,10(8):839-853
There are numerous conflicting epidemiological studies addressing correlations between cytochrome P450 1A1 (CYP1A1) genetic polymorphisms and lung cancer susceptibility, with associations plausibly linked to alterations in carcinogen bioactivation. Similarly, correlations between aryl hydrocarbon receptor gene (AHR) codon 554 genotype and CYP1A1 inducibility are controversial. The objective of this study was to determine whether smoking status, and CYP1A1, AHR, and glutathione S-transferase M1 gene (GSTM1) polymorphisms correlate with altered CYP1A1 activities. Lung microsomal CYP1A1-catalyzed 7-ethoxyresorufin O-dealkylation (EROD) activities were much higher in tissues from current smokers (n = 46) than in those from non-/former smokers (n = 24; 12.11 +/- 13.46 and 0.77 +/- 1.74 pmol/min/mg protein, respectively, mean +/- SD; P < 0.05). However, EROD activities in lung microsomes from current smokers CYP1A1*1/1 (n = 33) and heterozygous MspI variant CYP1A1*1/2A (n = 10) were not significantly different (12.23 +/- 13.48 and 8.23 +/- 9.76 pmol/min/mg protein, respectively, P > 0.05). Three current smokers were heterozygous variant CYP1A1*1/2B (possessing both *2A and *2C alleles), and exhibited activities similar to individuals CYP1A*1/1. One current smoker was heterozygous variant CYP1A1*4 and exhibited activities comparable with individuals CYP1A1*1/1 at that locus. EROD activities in microsomes from current smokers AHR(554)Arg/Arg (n = 41) and heterozygous variant AHR(554)Arg/Lys (n = 5) were not significantly different (12.13 +/- 13.56 and 12.01 +/- 14.23 pmol/min/mg protein, respectively; P > 0.05). Furthermore, microsomal EROD activities from current smokers with the GSTM1-null genotype (n = 28) were not significantly different from those (n = 18) carrying at least one copy of GSTM1 (12.61 +/- 14.24 and 11.34 +/- 12.53 pmol/min/mg protein, respectively; P > 0.05). Additionally, when genotypic combinations of CYP1A1, AHR, and GSTM1 were assessed, there were no significant effects on EROD activity. On the basis of microsomal enzyme activities from heterozygotes, CYP1A1*1/2A, CYP1A1*1/2B, CYP1A1*1/4, and AHR(554) Arg/Lys variants do not appear to significantly affect CYP1A1 activities in human lung, and we observed no association between CYP1A1 activity and the GSTM1-null polymorphism. 相似文献
16.
Differences in aromatic-DNA adduct levels between alveolar macrophages and subpopulations of white blood cells from smokers 总被引:8,自引:6,他引:8
Godschalk RW; Maas LM; Van Zandwijk N; van't Veer LJ; Breedijk A; Borm PJ; Verhaert J; Kleinjans JC; van Schooten FJ 《Carcinogenesis》1998,19(5):819-825
The 32P-post-labelling assay for DNA adduct quantification gives the
opportunity to examine endogenous exposure to DNA reactive compounds. Most
human biomonitoring studies applied white blood cells (WBC) or cells
obtained by broncho-alveolar lavages (BAL) as source of DNA, but still it
is not clear what cell type represents the most reliable indicator for
exposure to cigarette smoke-associated genotoxins. At first, we examined
DNA adduct levels by means of nuclease P1 (NP1) enriched 32P-post-labelling
in separated WBC subpopulations after in vitro incubations for 18 h with 10
microM benzo[a]pyrene (B[a]P). DNA adduct levels were highest in monocytes
(10.7 +/- 2.9 adducts/10(8) nucleotides, n = 8), followed by lymphocytes
(5.9 +/- 1.7, n = 8), and granulocytes (0.5 +/- 0.2, n = 8). Secondly,
aromatic-DNA adduct levels were determined in BAL cells and WBC-subsets
from (non-)smoking volunteers. In smoking individuals, adduct levels were
in the ranking order: BAL cells (3.7 +/- 1.0, n = 5) > monocytes (2.0
+/- 0.5, n = 8) > or = lymphocytes (1.6 +/- 0.4, n = 8) >
granulocytes (0.8 +/- 0.2, n = 8) by NP1-enrichment and monocytes (9.0 +/-
3.2, n = 5) > or = lymphocytes (8.0 +/- 2.1, n = 6) > granulocytes
(2.1 +/- 0.3, n = 7) by butanol-enriched 32P-post-labelling. Aromatic-DNA
adduct levels were significantly higher in WBC-subsets of smokers as
compared with non- smokers, except for DNA adducts in granulocytes using
butanol enrichment. Thirdly, dose-response relationships were investigated
in mononuclear white blood cells (MNC, i.e. monocytes plus lymphocytes) and
BAL-cells of a larger group of smoking individuals (n = 78). Adduct levels
in MNC were related to daily exposure to cigarette-tar (r = 0.31, P <
0.01). Adduct levels in BAL cells seemed to be correlated with pack-years,
but after correction for age this relationship was lost. Butanol extraction
resulted in 5-6-fold higher DNA adduct levels in MNC, whereas butanol
extraction of BAL-DNA of the same individuals yielded only 2-fold higher
adduct levels. The two enrichment procedures of 32P-post-labelling were
correlated in BAL cells (r = 0.86, P < 0.001, n = 12). We conclude that
particularly MNC are good surrogates for the detection of smoking-related
DNA adducts.
相似文献
17.
F J van Schooten M J Hillebrand F E van Leeuwen N van Zandwijk H M Jansen L den Engelse E Kriek 《Carcinogenesis》1992,13(6):987-993
Smokers of cigarettes are exposed to a number of carcinogens, including polycyclic aromatic hydrocarbons (PAHs), and are at a high risk for lung cancer. PAHs exert their carcinogenic activity after metabolic activation to reactive intermediates that can damage DNA through adduct formation. Measuring DNA adducts in peripheral white blood cells (WBC) could serve as a means of monitoring human exposure to genotoxic agents and subsequently risk assessment. In this study, DNA from WBC obtained from 39 lung cancer patients was examined for PAH-DNA adducts both in an ELISA using a polyclonal antibody against benzo[a]pyrene 7,8-diol-9,10-epoxide (BPDE)-DNA and the 32P-post-labeling technique. The ELISA results showed BPDE-DNA antigenicity in WBC DNA from 12/38 (32%) patients and adduct levels ranged from 1.5 to greater than 150 adducts in 10(8) nucleotides. The autoradiographs of chromatograms of 32P-post-labeled digests of WBC DNA from the 38 patients showed a variety of adduct spots; relative adduct labeling (RAL) values ranged from 0.3 to 407 adducts in 10(8) nucleotides. In 18 of the 38 (47%) persons an adduct spot was detected that co-chromatographed with the major BPDE-DNA adduct (BPDE-dG); RAL values ranged from 0.03 to 382 adducts in 10(8) nucleotides. Correlations were not significant between the adduct levels in WBC and smoking habits, age or sex. From 20 patients of the same group lung tissue was collected at surgery and examined for PAH-DNA adducts by ELISA and 32P-post-labeling assay. No significant correlation was found between DNA adduct levels in blood and lung. This finding stresses the limitations of the use of WBC as a surrogate for adduct levels in the target organ. 相似文献
18.
Naturally occurring plant phenols such as tannic acid, quercetin, myricetin, and anthraflavic acid are known to inhibit the mutagenicity of several bay-region diol-epoxides of polycyclic aromatic hydrocarbons (PAHs). The binding of bay-region diol-epoxides of PAHs to target tissue DNA is thought to be essential for the initiation of cancer by these compounds. In this study we investigated the effect of these plant phenols on PAH-DNA adduct formation in the epidermis and lung of SENCAR mice. In vitro addition of tannic acid, quercetin, myricetin, and anthraflavic acid (25 microM) to an incubation system containing epidermal microsomes prepared from either control or 3-methylcholanthrene-pretreated mice inhibited benzo(a)pyrene binding to calf thymus DNA by 63-64, 38-43, 36-37, and 27-33%, respectively. A single topical application of tannic acid, quercetin, myricetin, and anthraflavic acid at a dose of 400 mumol/kg body weight resulted in the inhibition of [3H]benzo(a)pyrene binding to epidermal DNA (48-73%) and protein (51-63%). The same dose of these plant phenols (400 mumol/kg) caused even greater inhibition of (+/-)-[3H]-7 beta,8 alpha-dihydroxy-7,8-dihydrobenzo(a)pyrene and [3H]-7,12-dimethybenz(a)anthracene binding to epidermal DNA and protein. The formation of (+)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene-deoxyguanosine adducts was substantially diminished in both epidermis (62-86%) and lungs (38-84%). These results indicate that tannic acid, quercetin, myricetin, and anthraflavic acid are potent inhibitors of carcinogen binding to epidermal and lung DNA and suggest that these plant phenols could prove useful in modifying the risk of tumor induction by PAHs such as benzo(a)pyrene and 7,12-dimethylbenz(a)anthracene in these two tissues. 相似文献
19.
Association between survival after treatment for breast cancer and glutathione S-transferase P1 Ile105Val polymorphism 总被引:13,自引:0,他引:13
Sweeney C McClure GY Fares MY Stone A Coles BF Thompson PA Korourian S Hutchins LF Kadlubar FF Ambrosone CB 《Cancer research》2000,60(20):5621-5624
A glutathione S-transferase (GST) P1 polymorphism results in an amino acid substitution, Ile105Val; the Val-containing enzyme has reduced activity toward alkylating agents. Cancer patients with the variant enzyme may differ in removal of treatment agents and in outcomes of therapy. We evaluated survival according to GSTP1 genotype among women (n = 240) treated for breast cancer. Women with the low-activity Val/Val genotype had better survival. Compared with Ile/Ile, hazard ratios for overall survival were 0.8 (95% confidence interval, 0.5-1.3) for Ile/Val and 0.3 (95% confidence interval, 0.1-1.0) for Val/Val (P for trend = 0.04). Inherited metabolic variability may influence treatment outcomes. 相似文献
20.
Association between glutathione S-transferase pi polymorphisms and survival in patients with advanced nonsmall cell lung carcinoma 总被引:5,自引:0,他引:5
Lu C Spitz MR Zhao H Dong Q Truong M Chang JY Blumenschein GR Hong WK Wu X 《Cancer》2006,106(2):441-447
BACKGROUND: Glutathione S-transferase (GST) pi (GSTP1) is a detoxification enzyme with substrate specificity for both exogenous carcinogens and chemotherapy agents. Genetic polymorphisms of GSTP1 exon 5 (Ile105Val) and exon 6 (Ala114Val) appear to reduce this enzyme's activity. Previously, the authors reported that the exon 6 variant was associated with an increased risk of lung carcinoma, particularly among men, younger patients, and ever smokers. In this study, the authors hypothesized that variant GSTP1 genotype would result in reduced inactivation of chemotherapy agents and improved survival in patients with advanced-stage nonsmall cell lung carcinoma (NSCLC), a population that is likely to receive platinum-based chemotherapy. METHODS: Patients with Stage III and IV NSCLC who were enrolled in a molecular epidemiology study were identified, and a polymerase chain reaction-restriction fragment length polymorphism assay was used to genotype GSTP1 exons 5 and 6 in 424 patients and 425 patients, respectively. RESULTS: Patients who had the exon 6 variant genotype (Ala/Val or Val/Val) had significantly better survival compared with patients who had the wild type genotype (Ala/Ala; P = 0.037), with median survival of 16.1 months and 11.4 months, respectively. Multivariate analysis revealed a reduced adjusted hazard ratio (HR) of death associated with the exon 6 variant genotype of 0.75 (95% confidence interval [95% CI], 0.54-1.05). This protective association was observed in younger patients (younger than age 62 yrs; HR, 0.59; 95% CI, 0.57-0.97) and in males (HR, 0.64; 95% CI, 0.41-0.99). GSTP1 exon 5 genotype was not associated with survival. CONCLUSIONS: GSTP1 exon 6 variant genotypes may be associated with improved survival among patients with Stage III and IV NSCLC. 相似文献