Modulation of DNA adduct levels in human mononuclear white blood cells and granulocytes by CYP1A1, CYP2D6 and GSTM1 genetic polymorphisms

Butkiewicz, Dorota; Grzybowska, Ewa; Hemminki, Kari; Øvrebø, Steinar; Haugen, Aage; Motykiewicz, Grażyna; Chorazy, M

doi:10.1016/s1383-5718(98)00064-3

Cited by 67 publications

(29 citation statements)

References 34 publications

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“…GSTM1 detoxifies a variety of genotoxic agents (reviewed in Hayes and Pulford; Ref. 36) and a reduction in GSTM1 protein activity, due to the deletion polymorphism, has previously been shown to be associated with significantly elevated levels of DNA adducts in WBCs (37) and with higher levels of sister-chromatid exchange (38) compared with individuals with wild-type GSTM1 protein levels.…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms in Genes Involved in Homologous Recombination Repair Interact to Increase the Risk of Developing Acute Myeloid Leukemia

Seedhouse

Faulkner

Ashraf

et al. 2004

Clinical Cancer Research

152

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Purpose: Double-strand break repair via homologous recombination is essential in maintaining genetic integrity. RAD51 and XRCC3 are involved in the repair of DNA by this pathway, and polymorphisms have been identified in both the RAD51 (RAD51-G135C) and XRCC3 (XRCC3-Thr241Met) genes. The object of this study was to examine whether these polymorphisms may modulate susceptibility to the development of acute myeloid leukemia (AML), a disease that is characterized by genetic instability.Experimental Design: We studied the distribution of polymorphisms in RAD51 and XRCC3 in 216 cases of de novo AML, 51 cases of therapy-related AML (t-AML), and 186 control subjects using PCR followed by restriction enzyme digestion. The polymorphic deletion of the detoxification gene glutathione S-transferase M1 (GSTM1) was also examined by PCR.Results: The risk of the development of AML was found to be significantly increased when both variant RAD51-135C and XRCC3-241Met alleles are present [odds ratio (OR), 3.77; 95% confidence interval (CI), 1.39 -10.24], whereas the risk of t-AML development is even higher (OR, 8.11; 95% CI, 2.22-29.68), presumably because of the large genotoxic insult these patients receive after their exposure to radiotherapy or chemotherapy. If we further divide the AML group into patients in which the burden of DNA damage is increased, because of the deletion of the GSTM1 gene, the risk of development of AML is further increased (OR, 15.26; 95% CI, 1.83-127.27). Conclusions:These results strongly suggest that DNA double-strand breaks and their repair are important in the pathogenesis of both de novo and t-AML.

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Section: Introductionmentioning

confidence: 99%

Polymorphisms in Genes Involved in Homologous Recombination Repair Interact to Increase the Risk of Developing Acute Myeloid Leukemia

Seedhouse

Faulkner

Ashraf

et al. 2004

Clinical Cancer Research

152

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Section: Introductionmentioning

confidence: 99%

“…On the contrary, Rothman et al (1995 ) saw a trend towards lower PAH -DNA adduct level in WBCs in fire fighters with either inactive GSTM1 or inducible CYP1A1 genotype. Some studies have revealed an effect of the exon 7 mutation in CYP1A1 on DNA adducts in WBCs (Butkiewicz et al, 1998;Mooney et al, 1997 ).The objective of the present study is to investigate if genetic polymorphism in enzymes involved in PAH metabolism have any influence on biomarkers of exposure, i.e., urine mutagenicity, 1 -OHP, and aromatic DNA adducts among coke oven workers. The study population is heavily exposed to PAHs ( Kuljukka et al, 1997 ).…”

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confidence: 95%

The effect of relevant genotypes on PAH exposure-related biomarkers

Kuljukka-Rabb

Nylund

Vaaranrinta

et al. 2002

J Expo Sci Environ Epidemiol

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Polycyclic aromatic hydrocarbons ( PAHs ) in coke oven emissions cause a cancer risk to humans. In a comprehensive biomonitoring study among Estonian coke oven workers, we looked at the effect of genetic polymorphisms in metabolic enzymes on urinary mutagenicity, 1 -hydroxypyrene ( 1 -OHP ) concentration in urine, and aromatic DNA adducts in white blood cells ( WBCs ). Coke oven workers were sampled twice ( samplings I and II ), and controls only once at the time of sampling I. Urinary mutagenicity was measured using the Ames test. CYP1A1, microsomal epoxide hydrolase ( mEH ), and glutathione S -transferase ( GST ) genotypes were analyzed by polymerase chain reaction ( PCR ). Urinary mutagenicity did not differ between exposed and controls, but those coke oven workers who were smokers had significantly higher ( P= 0.0002 ) mutagenic activity in urine than nonsmokers. Urinary mutagenicity was moderately correlated to levels of 1 -OHP and aromatic DNA adducts, the P values ranging from 0.0005 to 0.002. Carriers of a variant allele in exon 4 of mEH ( Arg 139 ) had elevated urinary mutagenicity ( sampling I ). In addition, urine mutagenicity of persons with predicted high mEH activity was significantly higher. Smoking habit did not explain the differences observed in urinary mutagenicity between mEH phenotype or genotype subgroups. Variation in exon 3 of mEH ( His 113 ) was related to a significantly ( P= 0.01 ) higher 1 -OHP concentration in exposed workers ( sampling II ). Workers from sampling I who had an Arg 139 variation in mEH had lower levels of adducts in lymphocytes ( P= 0.01 ) than others, while airborne benzo[ a ]pyrene ( B[ a ]P ) and His 113 variation affected interactively on adduct levels. Our study shows that a comprehensive assessment of exposure is essential for elucidation of PAH exposure at a workplace. Even at high exposures metabolic polymorphisms seem to have some effect on biomarker levels, and should be assessed in biomonitoring studies. Journal of Exposure Analysis and Environmental Epidemiology ( 2002 ) 12, 81 -91 DOI: 10.1038 / sj / jea / 7500204Keywords: aromatic DNA adducts, coke oven workers, genetic polymorphism, 1 -hydroxypyrene, urine mutagenicity. IntroductionEpidemiological data show that exposure to polycyclic aromatic hydrocarbons (PAHs ) is possibly carcinogenic to humans and believed to be mainly responsible for an elevated lung cancer incidence among coke oven workers (International Agency for Research on Cancer (IARC ), 1983;( International Agency for Research on Cancer (IARC ), 1984 ). In addition, other carcinogens, such as aromatic amines and heterocyclic compounds, are known to be present in coke oven emissions (IARC, 1984). Recent studies reveal both high and low mean exposure levels in operating coke oven plants.Most carcinogenic chemicals, such as PAHs, need to be activated to electrophilic reactants by metabolism in vivo (Miller and Miller, 1981 ). It is known at present that many of the genes coding enzymes involved in activation and detoxification of PAHs are poly...

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“…Several investigations have suggested an increased sensitivity of the GSTM1 null genotype to genotoxicity induced by various exposures, including tobacco smoke (35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47). Such an association was not, however, unequivocally demonstrated in most of the few studies where SCEs or MN were used as biomarkers (48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58).…”

Section: Discussionmentioning

confidence: 99%

Sister chromatid exchanges and micronuclei in peripheral lymphocytes of shoe factory workers exposed to solvents.

Pitarque

Vaglenov

Nosko

et al. 2002

Environ Health Perspect

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We examined sister chromatid exchanges (SCEs) and micronuclei (MN; cytokinesis-block method) in cultured peripheral lymphocytes from 52 female workers of two shoe factories and from 36 unexposed age- and sex-matched referents. The factory workers showed an elevated level of urinary hippuric acid, a biomarker of toluene exposure, and workplace air contained high concentrations of various organic solvents such as toluene, gasoline, acetone, and (in one of the plants only) ethylacetate and methylenediphenyl diisocyanate. The shoe factory workers showed a statistically significant higher frequency of micronucleated binucleate lymphocytes in comparison with the referents. This finding agreed with three preliminary MN determinations (each comprising 27-32 shoe workers and 16-20 controls) performed in one of the plants 2-5 years earlier. The shoe factory workers also had a lower average level of blood hemoglobin than the referents. In contrast, no difference was found between the groups in SCE analysis. Smokers showed significantly higher mean frequencies of SCEs per cell and high frequency cells (HFC) than nonsmokers. Aging was associated with increased MN rates and reduced cell proliferation. Polymorphism of the glutathione S-transferase M1 gene (GSTM1) did not affect the individual level of SCEs; but in smoking shoe workers an effect of the occupational exposure on the frequency of micronucleated cells could be seen only in GSTM1 null subjects. The low prevalence of the glutathione S-transferase T1 (GSTT1) null genotype precluded the evaluation of the influence of GSTT1 polymorphism. Our results show that the shoe factory workers have experienced genotoxic exposure, which is manifest as an increase in the frequency of MN, but not of SCEs, in peripheral lymphocytes. The exposures responsible for the MN induction could not be identified with certainty, but exposure to benzene in gasoline and methylenediphenyl diisocyanate may explain some of the findings.

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Modulation of DNA adduct levels in human mononuclear white blood cells and granulocytes by CYP1A1, CYP2D6 and GSTM1 genetic polymorphisms

Cited by 67 publications

References 34 publications

Polymorphisms in Genes Involved in Homologous Recombination Repair Interact to Increase the Risk of Developing Acute Myeloid Leukemia

Polymorphisms in Genes Involved in Homologous Recombination Repair Interact to Increase the Risk of Developing Acute Myeloid Leukemia

The effect of relevant genotypes on PAH exposure-related biomarkers

Sister chromatid exchanges and micronuclei in peripheral lymphocytes of shoe factory workers exposed to solvents.

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