2-Amino-9H-pyrido[2,3-b]indole (AαC) Adducts and Thiol Oxidation of Serum Albumin as Potential Biomarkers of Tobacco Smoke

Pathak, Khyatiben V.; Bellamri, Medjda; Wang, Yi; Langouët, Sophie; Turesky, Robert J.

doi:10.1074/jbc.m115.646539

Cited by 18 publications

(37 citation statements)

References 68 publications

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“…Some carcinogens generated during the combustion of tobacco contribute to oxidation. For example, 2-amino-9 H -pyrido [2,3- b ]indole (abbreviated as AαC) becomes activated in vivo to form N-oxidized metabolites that covalently bind to DNA (DNA adducts) and albumin (albumin adducts), promoting mutations and loss of function [ 104 ]. Normal albumin, the most abundant protein in human serum, normally serves as an anti-oxidant because it scavenges ROS generated during cell metabolism or introduced from the environment.…”

Section: Tobacco Smoke As a Modulator Of The Oxidants/anti-oxidants Bmentioning

confidence: 99%

Reactive oxygen species in organ-specific autoimmunity

Dalmazi

Hirshberg

Lyle

et al. 2016

Autoimmun Highlights

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Reactive oxygen species (ROS) have been extensively studied in the induction of inflammation and tissue damage, especially as it relates to aging. In more recent years, ROS have been implicated in the pathogenesis of autoimmune diseases. Here, ROS accumulation leads to apoptosis and autoantigen structural changes that result in novel specificities. ROS have been implicated not only in the initiation of the autoimmune response but also in its amplification and spreading to novel epitopes, through the unmasking of cryptic determinants. This review will examine the contribution of ROS to the pathogenesis of four organ specific autoimmune diseases (Hashimoto thyroiditis, inflammatory bowel disease, multiple sclerosis, and vitiligo), and compare it to that of a better characterized systemic autoimmune disease (rheumatoid arthritis). It will also discuss tobacco smoking as an environmental factor endowed with both pro-oxidant and anti-oxidant properties, thus capable of differentially modulating the autoimmune response.

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Section: Tobacco Smoke As a Modulator Of The Oxidants/anti-oxidants Bmentioning

confidence: 99%

Reactive oxygen species in organ-specific autoimmunity

Dalmazi

Hirshberg

Lyle

et al. 2016

Autoimmun Highlights

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“…20 On the basis of our understanding of 4-ABP metabolism in rodent and canine models, 32,67–69 we surmise that the amount of HONH-4-ABP circulating in blood and delivered to the erythrocyte is far greater than that of HONH-AαC, resulting in proportionately higher levels of 4-ABP-Hb adducts. 25,33 The N -hydroxylated metabolites of 4-ABP and AαC form adducts with human or rat serum albumin 64,70–72 In the case of 4-ABP, the binding of its N-oxidized metabolite is 250 fold-greater for Hb than for albumin in the rat model; 70,73 however, the comparative levels of HONH-AαC binding to Hb and albumin have not been measured in vivo in rodents or humans. The covalent (or non-covalent) binding of HONH-AαC to drug binding sites of albumin may be favored because of the planar nature of its fused 3-ring system, as opposed to the non-planar 4-ABP, and impact the relative levels of adduct formation between these two blood proteins.…”

Section: Discussionmentioning

confidence: 99%

Quantification of Hemoglobin and White Blood Cell DNA Adducts of the Tobacco Carcinogens 2-Amino-9H-pyrido[2,3-b]indole and 4-Aminobiphenyl Formed in Humans by Nanoflow Liquid Chromatography/Ion Trap Multistage Mass Spectrometry

Cai

Bellamri

Ming³

et al. 2017

Chem. Res. Toxicol.

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Aromatic amines covalently bound to hemoglobin (Hb) as sulfinamide adducts at the cysteine 93 residue of the Hb β chain have served as biomarkers to assess exposure to this class of human carcinogens for the past 30 years. In this study, we report that 2-amino-9H-pyrido[2,3-b]indole (AαC), an abundant carcinogenic heterocyclic aromatic amine formed in tobacco smoke and charred cooked meats, also reacts with Hb to form a sulfinamide adduct. A novel nanoflow liquid chromatography/ion trap multistage mass spectrometry (nanoLC-IT/MS3) method was established to assess exposure to AαC and the tobacco-associated bladder carcinogen 4-aminobiphenyl (4-ABP) through their Hb sulfinamide adducts. Following mild acid hydrolysis of Hb in vitro, the liberated AαC and 4-ABP were derivatized with acetic anhydride to form the N-acetylated amines, which were measured by nanoLC-IT/MS3. The limits of quantification (LOQ) for AαC- and 4-ABP-Hb sulfinamide adducts were ≤ 7.1 picograms per gram Hb. In a pilot study, the mean level of Hb sulfinamide adducts of AαC and 4-ABP, were, respectively, 3.3-fold and 4.8-fold higher in smokers (> 20 cigarettes/day) than nonsmokers. In contrast, the major DNA adducts of 4-ABP, N-(2′-deoxyguanosin-8-yl)-4-aminobiphenyl, and AαC, N-(2′-deoxyguanosin-8-yl)-2-amino-9H-pyrido[2,3-b]indole, were below the LOQ (3 adducts per 109 bases) in white blood cell (WBC) DNA of smokers and nonsmokers. These findings reaffirm that tobacco smoke is a major source of exposure to AαC. Hb sulfinamide adducts are suitable biomarkers to biomonitor 4-ABP and AαC; however, neither carcinogen binds to DNA in WBC, even in heavy smokers, at levels sufficient for biomonitoring.

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“…91 Therefore, careful manual inspection of the product ion spectra and the search for unique fragment ions attributed to the toxicant can help to identify adducted peptide precursor ions. 81,91,165 …”

Section: Analytical Ms-based Instruments and Scanning Techniques To Cmentioning

confidence: 99%

“…More recently, PhIP and 2-amino-9 H -pyrido[2,3- b ]indole (AαC), another HAA carcinogen present in tobacco smoke and well-done cooked meats, 124 were shown to react with the Cys34 of human Alb to form sulfinamide and sulfonamide adducts in vitro (Figure 6). 91,165,195 These adducts were sufficiently stable to characterize the following trypsin/chymotrypsin digestion as LQQC*PF or the missed-cleavage peptide LQQC*PFEDHVK by LC-MS/MS (Figure 7). An acid-labile Alb adduct of PhIP was reported in a cohort in Italy.…”

Section: Albumin Adducts Formed With Toxicants and Carcinogensmentioning

confidence: 99%

Biomonitoring Human Albumin Adducts: The Past, the Present, and the Future

Sabbioni¹,

Turesky

2016

Chem. Res. Toxicol.

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105

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Serum albumin (Alb) is the most abundant protein in blood plasma. Alb reacts with many carcinogens and/or their electrophilic metabolites. Studies conducted over 20 years ago showed that Alb forms adducts with the human carcinogens aflatoxin B1 and benzene, which were successfully used as biomarkers in molecular epidemiology studies designed to address the role of these chemicals in cancer risk. Alb forms adducts with many therapeutic drugs or their reactive metabolites such as β-lactam antibiotics, acetylsalicylic acid, acetaminophen, nonsteroidal anti-inflammatory drugs, chemotherapeutic agents, and antiretroviral therapy drugs. The identification and characterization of the adduct structures formed with Alb have served to understand the generation of reactive metabolites and to predict idiosyncratic drug reactions and toxicities. The reaction of candidate drugs with Alb is now exploited as part of the battery of screening tools to assess the potential toxicities of drugs. The use of gas chromatography-mass spectrometry, liquid chromatography, or liquid chromatography-mass spectrometry (LC-MS) enabled the identification and quantification of multiple types of Alb xenobiotic adducts in animals and humans during the past three decades. In this perspective, we highlight the history of Alb as a target protein for adduction to environmental and dietary genotoxicants, pesticides, and herbicides, common classes of medicinal drugs, and endogenous electrophiles, and the emerging analytical mass spectrometry technologies to identify Alb-toxicant adducts in humans.

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2-Amino-9H-pyrido[2,3-b]indole (AαC) Adducts and Thiol Oxidation of Serum Albumin as Potential Biomarkers of Tobacco Smoke

Cited by 18 publications

References 68 publications

Reactive oxygen species in organ-specific autoimmunity

Reactive oxygen species in organ-specific autoimmunity

Quantification of Hemoglobin and White Blood Cell DNA Adducts of the Tobacco Carcinogens 2-Amino-9H-pyrido[2,3-b]indole and 4-Aminobiphenyl Formed in Humans by Nanoflow Liquid Chromatography/Ion Trap Multistage Mass Spectrometry

Biomonitoring Human Albumin Adducts: The Past, the Present, and the Future

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