Use of human peripheral blood lymphocytes to measure DNA binding capacity of chemical carcinogens.

Gupta, Ramesh C.; Earley, Karen; Sharma, Surrendra

doi:10.1073/pnas.85.10.3513

Cited by 59 publications

(25 citation statements)

References 9 publications

(10 reference statements)

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“…DNA was isolated from peripheral blood and its concentration was measured as described by (Gupta et al, 1988). Genotyping for all studied loci was performed by PCR-RFLP method.…”

Section: Genotypingmentioning

confidence: 99%

MDM2 T309G has a Synergistic Effect with P21 ser31arg Single Nucleotide Polymorphisms on the Risk of Acute Myeloid Leukemia

Ebid¹,

Sedhom²,

El-Gammal³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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Background: The P53 tumor suppressor gene plays a pivotal role in maintaining cellular homeostasis by preventing the propagation of genome mutations. P53 in its transcriptionally active form is capable of activating distinct target genes that contribute to either apoptosis or growth arrest, like P21. However, the MDM2 gene is a major negative regulator of P53. Single nucleotide polymorphisms (SNP) in codon Arg72Pro of P53 results in impairment of the tumor suppressor activity of the gene. A similar effect is caused by a SNP in codon 31 of P21. In contrast, a SNP in position 309 of MDM2 results in increased expression due to substitution of thymine by guanine. All three polymorphisms have been associated with increased risk of tumorigenesis. Aim of the study: We aimed to study the prevalence of SNPs in the P53 pathway involving the three genes, P53, P21 and MDM2, among acute myeloid leukemia (AML) patients and to compare it to apparently normal healthy controls for assessment of impact on risk. Results: We found that the P21 ser31arg heterozygous polymorphism increases the risk of AML (P value=0.017, OR=2.946, 95% CI=1.216-7.134). Although the MDM2 309G allele was itself without affect, it showed a synergistic effect with P21 ser/arg polymorphism (P value=0.003, OR= 6.807, 95% CI= 1.909-24.629). However, the MDM2 309T allele abolish risk effect of the P21 polymorphic allele (P value= 0.71). There is no significant association of P53 arg72pro polymorphism on the risk of AML. Conclusion: We suggest that SNPs in the P53 pathway, especially the P21 ser31arg polymorphism and combined polymorphisms especially the P21/ MDM2 might be genetic susceptibility factors in the pathogenesis of AML.

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“…DNA was isolated from peripheral blood and its concentration was measured as described by (Gupta et al, 1988). Genotyping for all studied loci was performed by PCR-RFLP method.…”

Section: Genotypingmentioning

confidence: 99%

MDM2 T309G has a Synergistic Effect with P21 ser31arg Single Nucleotide Polymorphisms on the Risk of Acute Myeloid Leukemia

Ebid¹,

Sedhom²,

El-Gammal³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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“…Therefore, DNA adducts have predominantly been studied in easily available peripheral white blood cells (WBC). Gupta et al (1988) demonstrated the capacity of human peripheral blood lymphocytes to in vitro metabolize a number of carcinogens, including B[α]P, to their DNA binding species and high inter-individual variations (up to 62 fold) in binding capacity of reactive PAH derivatives were observed. This variation in B[a]P related DNA adduct formation in vitro was found to be genetically controlled (Nowak et al, 1988) and may be indicative for individual differences in lung cancer susceptibility (Hawke et al, 1986;Nowak et al, 1992).…”

Section: Studies In Humansmentioning

confidence: 99%

A Critical Evaluation of DNA Adducts as Biological Markers for Human Exposure to Polycyclic Aromatic Compounds

Godschalk¹,

Schooten²,

Bartsch³

2003

BMB Reports

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The causative role of polycyclic aromatic hydrocarbons (PAH) in human carcinogenesis is undisputed. Measurements of PAH-DNA adduct levels in easily accessible white blood cells therefore represent useful early endpoints in exposure intervention or chemoprevention studies. The successful applicability of DNA adducts as early endpoints depends on several criteria: i. adduct levels in easily accessible surrogate tissues should reflect adduct levels in target-tissues, ii. toxicokinetics and the temporal relevance should be properly defined. iii. sources of interand intra-individual variability must be known and controllable, and finally iv. adduct analyses must have advantages as compared to other markers of PAHexposure. In general, higher DNA adduct levels or a higher proportion of subjects with detectable DNA adduct levels were found in exposed individuals as compared with nonexposed subjects, but saturation may occur at high exposures. Furthermore, DNA adduct levels varied according to changes in exposure, for example smoking cessation resulted in lower DNA adduct levels and adduct levels paralleled seasonal variations of air-pollution. Intraindividual variation during continuous exposure was low over a short period of time (weeks), but varied significantly when longer time periods (months) were investigated. Inter-individual variation is currently only partly explained by genetic polymorphisms in genes involved in PAH-metabolism and deserves further investigation. DNA adduct measurements may have three advantages over traditional exposure assessment: i. they can smooth the extreme variability in exposure which is typical for environmental toxicants and may integrate exposure over a longer period of time. Therefore, DNA adduct assessment may reduce the monitoring effort. ii. biological monitoring of DNA adducts accounts for all exposure routes. iii. DNA adducts may account for inter-individual differences in uptake, elimination, distribution, metabolism and repair amongst exposed individuals. In conclusion, there is now a sufficiently large scientific basis to justify the application of DNA adduct measurements as biomarkers in exposure assessment and intervention studies. Their use in risk-assessment, however, requires further investigation.

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“…lc, adduct4). Previous studies indicate that human lymphocytes can metabolize single chemicals as well as complex air pollution particle extracts (13,14). Future studies to evaluate the differences in labeling efficiency by comparing DNA adduct patterns in the nuclease P1 and butanol extraction versions of the postlabeling assay may reveal evidence for the presence ofadditional N-substituted arylamine adducts resulting from the nitroreduction ofnitrated PAH present in diesel extracts.…”

Section: In Vivo Treatmentsmentioning

confidence: 92%

Detection and comparison of DNA adducts after in vitro and in vivo diesel emission exposures.

Gallagher

George

Kohan

et al. 1993

Environ Health Perspect

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Development of methods to evaluate certain classes of polycyclic aromatic compounds (PAC) detected in complex mixtures to which humans are exposed would greatly inprove the dbgnostic potential of 32P-postlabeling analyss. Identification of DNA adduct patterns or specific exposur-related marker adducts wold strengthen associations between observed DNA adducts and exposures to different environmental pollutants (e.g., kerosene, cigarette smoke, coke oven, and diesel). We have compared diesel-modified DNA adduct patterns in various in vitro and in vivo rodent model systems and compared them to DNA reactive oxidative and reductive metabolites of 1-nitropyrene. The formation of nitrated polycyclic aromatic hydrocarbon (nitrated PAH) DNA adducts, derived from themetabolism of diesel eKtract constituents, was enhanced relative to other PAH-derived DNA adducts via xanthine oxidase-catalyzed nitroreduction. These adducts were detectable only by the butanol extraction version of the postlabding analysis. Tve major DNA adducts were detected in human lymphocytes treated in vitro with diesel extract. A major adduct detected in human lymphocytes treated in vitro with diesel extract comigrated with a major adduct detected in lymphocyte DNA treated with benzo[alpyrene (BaP) alone. Other adducts that co-migrated with the major BaP-derived adducts were detected in skin and lung DNA isolated fron rodents topicafly treated with (50 mg) diesel extract and the major adduct detected in calf thymus DNA treated with rat liver S9 and diesel particle extract. Pbstlabeling of lung DNA isolated from rodents exposed via lung inhalation for 24 months to diesel combustion emissions resulted in the fonnation ofa major nuclease-Pi-sensitive DNA adduct that did not co-migmte with the major BaP-diol epoxide adduct. Based on its sensitivity to nuclease-P1, this adduct may be an N-substituted aryl adduct. Marker adducts detected in the various test systems presented here will assist in characterizing nuclease-Pl-sensitive nitrated PAH adducts in humans.

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Use of human peripheral blood lymphocytes to measure DNA binding capacity of chemical carcinogens.

Cited by 59 publications

References 9 publications

MDM2 T309G has a Synergistic Effect with P21 ser31arg Single Nucleotide Polymorphisms on the Risk of Acute Myeloid Leukemia

MDM2 T309G has a Synergistic Effect with P21 ser31arg Single Nucleotide Polymorphisms on the Risk of Acute Myeloid Leukemia

A Critical Evaluation of DNA Adducts as Biological Markers for Human Exposure to Polycyclic Aromatic Compounds

Detection and comparison of DNA adducts after in vitro and in vivo diesel emission exposures.

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