Methemoglobin Formation and Characterization of Hemoglobin Adducts of Carcinogenic Aromatic Amines and Heterocyclic Aromatic Amines

Pathak, Khyatiben V.; Chiu, Ting-Lan; Amin, Elizabeth A.; Turesky, Robert J.

doi:10.1021/acs.chemrestox.5b00418

Cited by 40 publications

(50 citation statements)

References 76 publications

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“…51 The N -hydroxylated metabolites of MeIQx and PhIP did not react with the oxy-heme complex and induce met-Hb formation, and as a consequence, the chemical modification of the β-Cys 93 residue of Hb was negligible. 51 However, HONH-AαC induced methemoglobinemia and formed an Hb sulfinamide adduct in human erythrocytes at greater levels than HONH-4-ABP. 51 We also reported that AαC undergoes bioactivation and forms DNA adducts in human T lymphocytes in cell culture at higher levels than 4-ABP, PhIP and MeIQx.…”

Section: Resultsmentioning

confidence: 97%

“…51 However, HONH-AαC induced methemoglobinemia and formed an Hb sulfinamide adduct in human erythrocytes at greater levels than HONH-4-ABP. 51 We also reported that AαC undergoes bioactivation and forms DNA adducts in human T lymphocytes in cell culture at higher levels than 4-ABP, PhIP and MeIQx. 57 Therefore, we sought to determine if AαC underwent bioactivation in vivo to form a sulfinamide adduct with Hb using a novel nanoLC-IT/MS 3 platform.…”

Section: Resultsmentioning

confidence: 99%

“…31–33 The higher level of 4-ABP-Hb adduct formation is not attributed to the superior reactivity of the HONH-4-ABP with HbO 2 since HNOH-AαC induces more methemoglobinemia in erythrocytes and forms higher levels of the Hb-sulfinamide than does HONH-4-ABP. 51 Higher rates of N-oxidation of 4-ABP also do not appear to explain the elevated levels of 4-ABP-Hb formation. The rates of N-oxidation of 4-ABP and AαC are similar with human liver microsomes, 29,55 and AαC and 4-ABP form comparable levels of DNA adducts in primary human hepatocytes.…”

Section: Discussionmentioning

confidence: 95%

“…The levels of Hb modification with carcinogens were 63 ng of Hb-4-ABP sulfinamide and 190 ng Hb-AαC sulfinamide per 100 μg Hb, based on recovery of 4-ABP and AαC from modified Hb, following acid treatment ( vide infra ). 51 …”

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

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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Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 95%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

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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“…The formation of p -methylphenylhydroxylamine in DMPT-treated rats is inferred by the presence of N -methyl- p -toluidine and p -( N -acetylhydroxyamino)hippuric acid in the urine (Kim et al 2007). N -hydroxylated arylamines are also capable of covalently binding to hemoglobin and/or DNA (Marques et al 1997; Pathak et al 2016). DNA adduct formation may result in mutations leading to a carcinogenic response.…”

Section: Introductionmentioning

confidence: 99%

Hepatic transcriptomic alterations for N,N-dimethyl-p-toluidine (DMPT) and p-toluidine after 5-day exposure in rats

et al. 2016

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N,N-dimethyl-p-toluidine (DMPT), an accelerant for methyl methacrylate monomers in medical devices, was a liver carcinogen in male and female F344/N rats and B6C3F1 mice in a 2-year oral exposure study. p-Toluidine, a structurally-related chemical, was a liver carcinogen in mice but not in rats in an 18-month feed exposure study. In this current study, liver transcriptomic data was used to characterize mechanisms in DMPT and p-toluidine liver toxicity and for conducting benchmark dose (BMD) analysis. Male F344/N rats were exposed orally to DMPT or p-toluidine (0, 1, 6, 20, 60 or 120 mg/kg/day) for 5-days. The liver was examined for lesions and transcriptomic alterations. Both chemicals caused mild hepatic toxicity at 60 and 120 mg/kg and dose-related transcriptomic alterations in the liver. There were 511 liver transcripts differentially expressed for DMPT and 354 for p-toluidine at 120 mg/kg/day (false discovery rate threshold of 5%). The liver transcriptomic alterations were characteristic of an anti-oxidative damage response (activation of the Nrf2 pathway) and hepatic toxicity. The top cellular processes in gene ontology (GO) categories altered in livers exposed to DMPT or p-toluidine were used for BMD calculations. The lower confidence bound benchmark doses (BMDL) for these chemicals were 2 mg/kg/day for DMPT and 7 mg/kg/day for p-toluidine. These studies show the promise of using 5-day target organ transcriptomic data to identify chemical-induced molecular changes that can serve as markers for preliminary toxicity risk assessment.

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Evaluation of the Ecotoxicity of New Polyurethane Composites on Target Organisms for Aquatic and Atmospheric Environments

Corapi

Gallo

Lucadamo

et al. 2022

Enviro Toxic and Chemistry

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The present study investigated if new biocomposite materials, polyurethanes (PURs) added with functionalized cellulose fibers, produce potential toxic effects on two target organisms currently used in biomonitoring the quality of two different environmental compartments. Natural fibers were extracted from the species Spartium junceum L., a shrub commonly found in the southern region of the Mediterranean having a high cellulose content. All PURs produced were characterized by Fourier-transform infrared spectroscopy, and their structure was analyzed by scanning electron microscopy. We measured the effects of exposure to aromatic and aliphatic PUR composites (containing or not cellulose fibers) on the aquatic model organism Daphnia magna Straus, a freshwater crustacean (Cladocera), and a biomonitor of air quality, the fruticose epiphytic lichen Pseudevernia furfuracea (L.) Zopf. Leachates from aliphatic PUR composite not containing cellulose are more toxic to D. magna than all others, showing a slight acute toxicity in the case of the shortest exposure (24 h) and a moderate acute toxicity in the longer one (48 h). This effect is most likely due to the presence of free organic ammines and amides, which, in their turn, are immobilized in composites containing cellulosic fibers because of the considerable amount of chemical functional groups. Regarding lichens, both types of aliphatic PURs resulted in a toxic effect. Formulate not added with cellulose strongly promoted fungal peroxidation, whereas that which was functionalized affected the pigment concentration of the algal partner. Our results suggest that the use of cellulose in PUR production, in general, can limit the ecotoxicological effects on both test organisms and reduce the potential environmental impact due to this type of polymer.

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Methemoglobin Formation and Characterization of Hemoglobin Adducts of Carcinogenic Aromatic Amines and Heterocyclic Aromatic Amines

Cited by 40 publications

References 76 publications

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

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

Hepatic transcriptomic alterations for N,N-dimethyl-p-toluidine (DMPT) and p-toluidine after 5-day exposure in rats

Evaluation of the Ecotoxicity of New Polyurethane Composites on Target Organisms for Aquatic and Atmospheric Environments

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