Urinary excretion of 3-methyladenine and 3-ethyladenine after controlled exposure to tobacco smoke

Kopplin, Andrea; Eberle-Adamkiewicz, Gertrud; Glüsenkamp, Karl-Heinz; Nehls, Peter; Kirstein, Uwe

doi:10.1093/carcin/16.11.2637

Cited by 40 publications

(28 citation statements)

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“…The no smoking group also had a significantly lower level (p B/0.0001) of 3-MeAd than the CC2 group at day 8. The 3-MeAd excretion levels in CC1 and CC2 smokers were comparable with the data for smokers reported by Kopplin et al (1995), but those in the no smoking group was lower than in non-smokers ('passive smokers') reported by the same authors. For Evaluation of urinary biomarkers of exposure to cigarette smoke 45 Biomarkers Downloaded from informahealthcare.com by Mcgill University on 12/03/14 3-EtAd, the results are difficult to interpret because, first, the levels in the CC1 and no smoking groups did not show any significant change relative to their respective baselines; second, there was no detectable difference between the CC1 and no smoking groups either at baseline or at day 8; third, there was no within subjectcorrelation between baseline and day 8 for the CC1 group; and forth, the levels in the CC2, EHCSS1 and EHCSS2 groups decreased significantly relative to their respective baseline levels.…”

Section: -Mead and 3-etad As Biomarkerssupporting

confidence: 84%

“…Prevost et al (1993) reported rapid eliminations of deuterium labelled 3-MeAd and 3-EtAd in human following ingestion: within 24 h, /90% of 3-MeAd was excreted and 67 Á/74% of 3-EtAd was excreted. In the two reported controlled studies (Kopplin et al 1995, Prevost & Shuker 1996, immediate rising and falling of excretion levels of these alkyladenines in smokers on alternating smoking and no smoking days were observed, which is consistent with the normally rapid repair mechanisms following DNA alkylation. The high 3-EtAd excretion level in the no smoking group at day 8 could not be explained by dietary confounding either because the menus at baseline and at day 8 were identical.…”

Section: -Mead and 3-etad As Biomarkerssupporting

confidence: 70%

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Evaluation of urinary 1-hydroxypyrene,S-phenylmercapturic acid,trans,trans-muconic acid, 3-methyladenine, 3-ethyladenine, 8-hydroxy-2′-deoxyguanosine and thioethers as biomarkers of exposure to cigarette smoke

Feng¹,

Roethig²,

Liang³

et al. 2006

Biomarkers

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The objective was to evaluate the utility of urinary 1-hydroxypyrene (1-OHP), S-phenylmercapturic acid (S-PMA), trans,trans-muconic acid (t,t-MA), 3-methyladenine (3-MeAd), 3-ethyladenine (3-EtAd), 8-hydroxy-2'-deoxyguanosine (8-OHdG) and thioethers as biomarkers for assessing the exposure in adult smokers who switched from smoking conventional cigarettes to candidate potential reduced exposure products (PREP) or who stopped smoking. Two electrically heated smoking systems (EHCSS) were used as prototype cigarettes that have significant reductions in a number of mainstream smoke constituents as measured by smoking machines relative to those from conventional cigarettes. Urine samples were collected from a randomized, controlled, forced-switching study in which 110 adult smokers of a conventional cigarette brand (CC1) were randomly assigned to five study groups. The groups included the CC1 smoking group, a lower-tar conventional cigarette (CC2) smoking group, EHCSS1 group, EHCSS2 group and a no smoking group that were monitored for 8 days. Biomarkers were measured at baseline and day 8. The daily excretion levels of these biomarkers were compared among the groups before and after switching, and the relationships between the daily excretion levels of these biomarkers and cigarette smoking-related exposure were investigated using Pearson product-moment correlation and multiple regression analyses. It was concluded that under controlled study conditions: (1) 1-OHP, S-PMA and t,t-MA are useful biomarkers that could differentiate exposure between smoking conventional and EHCSS cigarettes or between smoking conventional cigarettes and no smoking; between S-PMA and t,t-MA, the former appeared to be more sensitive; (2) 3-MeAd could only differentiate between smoking conventional cigarettes and no smoking; the results for 3-EtAd were not conclusive because contradictory results were observed; (3) 8-OHdG had a questionable association with smoking and therefore the utility of this biomarker for smoking-related exposure could not be established; and (4) urinary excretion of thioethers as a biomarker lacked sensitivity to demonstrate a clear dose-response relationship in conventional cigarette smokers, although it could differentiate the excretion levels between those subjects who smoked a conventional cigarette and those who stopped smoking.

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Section: -Mead and 3-etad As Biomarkerssupporting

confidence: 84%

Section: -Mead and 3-etad As Biomarkerssupporting

confidence: 70%

Evaluation of urinary 1-hydroxypyrene,S-phenylmercapturic acid,trans,trans-muconic acid, 3-methyladenine, 3-ethyladenine, 8-hydroxy-2′-deoxyguanosine and thioethers as biomarkers of exposure to cigarette smoke

Feng¹,

Roethig²,

Liang³

et al. 2006

Biomarkers

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“…Point mutations induced by alkylating agents originate principally from O 6 -alkylguanine and O 4 -alkylthymine (10). Alkylated adenine derivatives have been found in the urine of smokers (11) and procarcinogenic DNA adducts that arise from exposure to methylating agents have been detected in human colorectal DNA at levels comparable with those that cause adverse effects in model systems (2).…”

mentioning

confidence: 99%

DNA Repair Polymorphisms and Risk of Colorectal Adenomatous or Hyperplastic Polyps

Bigler

Ulrich

Kawashima

et al. 2005

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Genetic variability in DNA repair genes may contribute to differences in DNA repair capacity and susceptibility to cancer, especially in the presence of exposures such as smoking. In a Minnesota-based case-control study of cases with only adenomatous polyps (n = 384), only hyperplastic polyps (n = 191), or both types of polyps (n = 119) versus polyp-free controls (n = 601), we investigated the role of polymorphisms in the DNA repair genes O 6 -methylguanine methyltransferase (MGMT; p.L84F and p.I143V), XPD (p.D312N and p.K751Q), and XPG (p.D1104H). MGMT polymorphisms were not associated with polyp risk. Overall, a homozygous variant XPD -combined genotype was associated with an increased risk of adenomatous polyps [odds ratio (OR), 1.57; 95% confidence interval (95% CI), 1.04-2.38] and an XPGHH1104 genotype with a decreased risk of hyperplastic polyps (OR, 0.36; 95% CI, 0.13-0.98). However, age stratification showed that the XPD association was present only in subjects z60 years old (OR, 3.77; 95% CI, 1.94-7.35), whereas the XPG association was observed largely in subjects <60 years old (OR, 0.20; 95% CI, 0.05-0.91). Smokers did not have a significantly increased risk of adenomatous polyps in the absence of synchronous hyperplastic polyps, except for subjects with a homozygous variant XPD genotype or a homozygous wild-type XPG genotype (OR, 3.93; 95% CI, 1.68-9.21 and OR, 1.59; 95% CI, 1.01-2.50, respectively). Smoking was associated with a statistically significant 2.5-to 6-fold increased risk of hyperplastic polyps for individuals with most of the DNA repair genotypes. However, no substantial increase was observed among individuals who were homozygous variant for XPG (1104HH; OR, 1.38; 95% CI, 0.25-7.65). Our data suggest that polymorphisms in DNA repair genes may be risk factors for colorectal neoplasia and that they may exacerbate the effects of exposures to carcinogens. (Cancer Epidemiol Biomarkers Prev 2005; 14(11):2501 -8)

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“…DNA can be alkylated by a variety of agents that occur both exogenously and endogenously (2,3). Alkylating agents are used in some chemotherapy treatments, and alkylated DNA bases have been detected in the urine of smokers (4). AlkB catalyzes demethylation of DNA and along with AlkA, AidB, and Ada is one of four proteins involved in the adaptive response to alkylation damaged DNA in Escherichia coli (5).…”

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confidence: 99%

The Selectivity and Inhibition of AlkB

Welford¹,

Schlemminger²,

McNeill³

et al. 2003

Journal of Biological Chemistry

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AlkB is one of four proteins involved in the adaptive response to DNA alkylation damage in Escherichia coli and is highly conserved from bacteria to humans. Recent analyses have verified the prediction that AlkB is a member of the Fe(II) and 2-oxoglutarate (2OG)-dependent oxygenase family of enzymes. AlkB mediates repair of methylated DNA by direct demethylation of 1-methyladenine and 3-methylcytosine lesions. Other members of the Fe(II) and 2OG-dependent oxygenase family, including those involved in the hypoxic response, are targets for therapeutic intervention. Assays measuring 2OG turnover were used to investigate the selectivity of AlkB. 1-Methyladenosine, 1-methyl-2 -deoxyadenosine, 3-methylcytidine, and 3-methyl-2 -deoxycytidine all stimulated 2OG turnover by AlkB but were not demethylated indicating an uncoupling of 2OG and prime substrate oxidation and that oligomeric DNA is required for hydroxylation and subsequent demethylation. In contrast the equivalent unmethylated nucleosides did not stimulate 2OG turnover indicating that the presence of a methyl group in the substrate is important in initiating oxidation of 2OG. Stimulation of 2OG turnover by 1-methyladenosine was highly dependent on the presence of a reducing agent, ascorbate or dithiothreitol. Following the observation that AlkB is inhibited by high concentrations of 2OG, analogues of 2OG, including 2-mercaptoglutarate, were found to specifically inhibit AlkB. The flavonoid quercetin inhibits both AlkB and the 2OG oxygenase factor-inhibiting hypoxia-inducible factor (FIH) in vitro. FIH inhibition by quercetin occurs in the presence of excess iron indicating a specific interaction, while the inhibition of AlkB by quercetin is, predominantly, due to nonspecific iron chelation.The integrity of the genome is maintained by a set of DNA repair enzymes, including those that repair alkylation damage (1). DNA can be alkylated by a variety of agents that occur both exogenously and endogenously (2, 3). Alkylating agents are used in some chemotherapy treatments, and alkylated DNA bases have been detected in the urine of smokers (4). AlkB catalyzes demethylation of DNA and along with AlkA, AidB, and Ada is one of four proteins involved in the adaptive response to alkylation damaged DNA in Escherichia coli (5). Ada, which has been termed the "suicidal repair protein," contains two active sites, one of which demethylates O 6 -methylguanine by irreversible transfer of the methyl group to a cysteine (5, 6).The second active site removes methyl groups from S-methyl phosphoesters by nucleophilic methylation of another cysteine residue (5,7,8). Methylation of the latter cysteine converts Ada into a strong transcriptional activator of both its own production and the other three proteins of the adaptive response (9). AlkA is a DNA glycosylase with a wide substrate selectivity, including excision of cytotoxic 3-methyladenine residues (10). AlkA "flips" the damaged base out of the DNA double helix by inserting Leu-125 into the position occupied by the damaged base (11)...

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Urinary excretion of 3-methyladenine and 3-ethyladenine after controlled exposure to tobacco smoke

Cited by 40 publications

References 0 publications

Evaluation of urinary 1-hydroxypyrene,S-phenylmercapturic acid,trans,trans-muconic acid, 3-methyladenine, 3-ethyladenine, 8-hydroxy-2′-deoxyguanosine and thioethers as biomarkers of exposure to cigarette smoke

Evaluation of urinary 1-hydroxypyrene,S-phenylmercapturic acid,trans,trans-muconic acid, 3-methyladenine, 3-ethyladenine, 8-hydroxy-2′-deoxyguanosine and thioethers as biomarkers of exposure to cigarette smoke

DNA Repair Polymorphisms and Risk of Colorectal Adenomatous or Hyperplastic Polyps

The Selectivity and Inhibition of AlkB

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