Formation of dna adducts and water‐soluble metabolites of benzo[a]pyrene in human monocytes is genetically controlled

Nowak, Dennis; U, Schmidt-Preuss; Jörres, Rudolf A.; Liebke, Frank; Rüdiger, H. W.

doi:10.1002/ijc.2910410202

Cited by 33 publications

(9 citation statements)

References 30 publications

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“…This is in line with the assumption that inter-individual variation in carcinogen metabolism is an important determinant of cancer susceptibility (Harris, 1991;Nowak et al, 1988). Theoretically, some arguments in favor of this model can be given; for example, some people drink and smoke excessively but never develop a tumor while others who drink and smoke less develop a tumor at an early age.…”

Section: Discussionmentioning

confidence: 55%

Increased mutagen sensitivity in head‐and‐neck squamous‐cell carcinoma patients, particularly those with multiple primary tumors

Cloos

Braakhuis

Steen

et al. 1994

Intl Journal of Cancer

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Mutagen sensitivity is a constitutional factor which may be used to identify head-and-neck squamous-cell carcinoma (HNSCC) patients at high risk for the development of multiple primary tumors (MPT). In this retrospective study, mutagen sensitivity was measured in HNSCC patients with a single primary tumor (SPT), HNSCC patients who have already developed MPT and control subjects with no tumor history. In vitro, lymphocytes were challenged with bleomycin and chromosomal damage was quantified by scoring chromatid breaks of 100 cells. A significant difference in the mean number of breaks per cell (b/c) was found between SPT patients and controls. Patients with MPT showed a significantly higher mean b/c value than SPT patients. This increase in mutagen sensitivity in HNSCC patients was not related to well-known cancer risk factors such as age, or life-style factors such as smoking and alcohol drinking habits. In addition, tumor site but not tumor stage was found to be related to mutagen sensitivity. On the basis of our findings, we propose that mutagen sensitivity is not an independent risk factor but a constitutional factor which reflects the way in which genotoxic compounds are dealt with and is thereby directly related to cancer risk.

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Section: Discussionmentioning

confidence: 55%

Increased mutagen sensitivity in head‐and‐neck squamous‐cell carcinoma patients, particularly those with multiple primary tumors

Cloos

Braakhuis

Steen

et al. 1994

Intl Journal of Cancer

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“…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). However, WBC are not necessarily target cells for PAH or the most sensitive cells for DNA adduct formation and the question remains whether these cells provide a reliable estimate of PAH exposure in vivo.…”

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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“…The metabolic activation process produces DNA adducts, which are critical in the carcinogenic process because they cause mutations in important growth control genes, such as KRAS and p53 (4, 9, 10). The metabolic activation of PAH to DNA adducts varies widely among individuals (11)(12)(13)(14)(15)(16)(17). These well-established facts lead to the major hypothesis that smokers who efficiently metabolically activate PAH will be at a higher risk for lung cancer.…”

Section: Introductionmentioning

confidence: 99%

Comparison of Polymorphisms in Genes Involved in Polycyclic Aromatic Hydrocarbon Metabolism with Urinary Phenanthrene Metabolite Ratios in Smokers

Hecht

Carmella

Yoder

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

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The hypothesis that interindividual differences among smokers in the metabolism of polycyclic aromatic hydrocarbons (PAH) are related to lung cancer risk has been extensively investigated in the literature. These studies have compared lung cancer risk in groups of smokers with or without polymorphisms in genes involved in PAH metabolism. We believe that carcinogen metabolite phenotyping, involving the actual measurement of PAH metabolites, would be a better way to investigate differences in lung cancer risk. With this goal in mind, we have developed methods for quantifying phenanthrene metabolites in urine. Phenanthrene is the simplest PAH with a bay region, a feature closely associated with carcinogenicity. The urinary metabolite r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene (PheT) is a measure of metabolic activation, whereas phenanthrols (HOPhe) are a measure of detoxification. In this study, we quantified urinary PheT/HOPhe ratios in 346 smokers who were also genotyped for 11 polymorphisms in genes involved in PAH metabolism: CYP1A1MspI, CYP1A1I462V, CYP1B1R48G, CYP1B1A119S, CYP1B1L432V, CYP1B1N453S, EPHX1Y113H, EPHX1H139R, GSTP1I105V, GSTP1A114V, and GSTM1 null. The geometric mean molar PheT/3-HOPhe ratio was 4.08 (95% confidence interval, 3.79-4.39). Ten percent of the smokers had PheT/3-HOPhe ratios of z9.90. We found a significant association between the presence of the CYP1A1I462V polymorphism and high PheT/3-HOPhe ratios (P = 0.02). This effect was particularly strong in females and in combination with the GSTM1 null polymorphism. In contrast, the CYP1B1R48G and CYP1B1A119S polymorphisms were associated with significantly lower PheT/3-HOPhe ratios, particularly in Blacks. There were no consistent significant effects of any of the other polymorphisms on PheT/3-HOPhe ratios. The highest 10% of PheT/3-HOPhe ratios could not be predicted by the presence of any of the 11 polymorphisms individually or by certain combinations. The effects of the CYP1A1I462 polymorphism observed here, particularly in combination with GSTM1 null, are quite consistent with reports in the literature. However, the results of this study indicate that genotyping is not an effective way to predict PAH metabolism at least as represented by PheT/HOPhe ratios.

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Formation of dna adducts and water‐soluble metabolites of benzo[a]pyrene in human monocytes is genetically controlled

Cited by 33 publications

References 30 publications

Increased mutagen sensitivity in head‐and‐neck squamous‐cell carcinoma patients, particularly those with multiple primary tumors

Increased mutagen sensitivity in head‐and‐neck squamous‐cell carcinoma patients, particularly those with multiple primary tumors

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

Comparison of Polymorphisms in Genes Involved in Polycyclic Aromatic Hydrocarbon Metabolism with Urinary Phenanthrene Metabolite Ratios in Smokers

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