Investigation of the genotoxic effects of 2-amino-9H-pyrido[2,3-b]indole in different organs of rodents and in human derived cells

Majer, Bernhard; Kassie, Fekadu; Sasaki, Yu; Pfau, Wolfgang; Glatt, Hansruedi; Meinl, Walter; Darroudi, F.; Knasmüller, Siegfried

doi:10.1016/j.jchromb.2003.10.042

Cited by 21 publications

(11 citation statements)

References 40 publications

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“…AαC is genotoxic in human lymphoblastoid cells (MLC-5) 21 and in peripheral blood lymphocytes cells, when assessed the by the comet and micronucleus assays. 22 We also showed that AαC forms high and persistent levels of DNA adducts in primary human hepatocytes. 23,24 The major DNA adduct formed by AαC is N -(deoxyguanosin-8-yl)-2-amino-9 H -pyrido[2,3- b ]indole (dG-C8-AαC) 25,26 which is regarded as a mutagenic lesion.…”

Section: Introductionmentioning

confidence: 66%

Metabolism of the Tobacco Carcinogen 2-Amino-9H-pyrido[2,3-b]indole (AαC) in Primary Human Hepatocytes

Bellamri

Hégarat

Turesky

et al. 2016

Chem. Res. Toxicol.

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2-Amino-9H-pyrido[2,3-b]indole (AαC) is the most abundant carcinogenic heterocyclic aromatic amine (HAA) formed in mainstream tobacco smoke. AαC is a liver carcinogen in rodents, but its carcinogenic potential in humans is not known. To obtain a better understanding of the genotoxicity of AαC in humans, we have investigated its metabolism and its ability to form DNA adducts in human hepatocytes. Primary human hepatocytes were treated with AαC at doses ranging from 0.1 to 50 μM and the metabolites were characterized by UPLC/ ion trap multistage mass spectrometry (UPLC/MSn). Six major metabolites were identified: a ring-oxidized doubly conjugated metabolite, N2-acetyl-2-amino-9H-pyrido[2,3-b]indole-6-yl-oxo-(β-D-glucuronic acid) (N2-acetyl-AαC-6-O-Gluc); two ring-oxidized glucuronide (Gluc) conjugates: 2-amino-9H-pyrido[2,3-b]indol-3-yl-oxo-(β-D-glucuronic acid) (AαC-3-O-Gluc) and 2-amino-9H-pyrido[2,3-b]indol-6-yl-oxo-(β-D-glucuronic acid) (AαC-6-O-Gluc); two sulfate conjugates, 2-amino-9H-pyrido[2,3-b]indol-3-yl sulfate (AαC-3-O-SO3H) and 2-amino-9H-pyrido[2,3-b]indol-6-yl sulfate (AαC-6-O-SO3H); and the Gluc conjugate, N2-(β-D-glucosidurony1)-2-amino-9H-pyrido[2,3-b]indole (AαC-N2-Gluc). In addition, four minor metabolites were identified: N2-acetyl-9H-pyrido[2,3-b]indol-3-yl sulfate (N2-acetyl-AαC-3-O-SO3H); N2-acetyl-9H-pyrido[2,3-b]indol-6-yl sulfate (N2-acetyl-AαC-6-O-SO3H), N2-acetyl-2-amino-9H-pyrido[2,3-b]indol-3-yl-oxo-(β-D-glucuronic acid) (N2-acetyl-AαC-3-O-Gluc), and O-(β-D-glucosidurony1)-2-hydroxyamino-9H-pyrido[2,3-b]indole (AαC-HN2-O-Gluc). The latter metabolite, AαC-HN2-O-Gluc is a reactive intermediate which binds to DNA to form the covalent adduct N-(2′-deoxyguanosin-8-yl)-2-amino-9H-pyrido[2,3-b]indole (dG-C8-AαC). Pre-incubation of hepatocytes with furafylline, a selective mechanism-based inhibitor of P450 1A2, resulted in a strong decrease in the formation of AαC-HN2-O-Gluc and a concomitant decrease in DNA adduct formation. Our findings describe the major pathways of metabolism of AαC in primary human hepatocytes and reveal the importance of N-acetylation and glucuronidation in metabolism of AαC. P450 1A2 is a major isoform involved in the bioactivation of AαC to form the reactive AαC-HN2-O-Gluc conjugate and AαC-DNA adducts.

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Section: Introductionmentioning

confidence: 66%

Metabolism of the Tobacco Carcinogen 2-Amino-9H-pyrido[2,3-b]indole (AαC) in Primary Human Hepatocytes

Bellamri

Hégarat

Turesky

et al. 2016

Chem. Res. Toxicol.

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“…The dose of A␣C (50 M) employed in human hepatocytes is greater than daily human exposure to A␣C but comparable with the doses employed in studies investigating the genotoxicity of A␣C (18,19). The amount of A␣C arising in mainstream smoke is 60 -250 ng/cigarette (7,8).…”

Section: Discussionmentioning

confidence: 87%

“…1) (17), which reacts with DNA to form covalent adducts, leading to mutations (18). The genotoxic potential of A␣C has been shown in human peripheral blood lymphocytes (19), Chinese hamster ovary cells (18), and human hepatocytes (20), where high levels of A␣C-DNA adducts are formed. However, long term stable biomarkers of A␣C must be developed for implementation in molecular epidemiology studies that seek to address a role for this chemical in human cancer risk.…”

mentioning

confidence: 99%

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

Pathak

Bellamri

Wang

et al. 2015

Journal of Biological Chemistry

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Background:The reactivity of A␣C, a tobacco smoke carcinogen, was investigated with DNA and albumin of human hepatocytes. Results: Hepatocytes bioactivate A␣C to metabolites, which adduct to DNA and albumin. Conclusion: Cys 34 and Met 329 of serum albumin are targets for A␣C electrophiles. Significance: A␣C forms macromolecular adducts and induces oxidative stress, which may be contributing factors to liver damage and cancer risk in smokers.

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“…are quite promising: Uhl et al (1999) carried out three independent repetitive SCGE experiments with IQ and B(a)P and found that the standard deviations between the results of the individual experiments were <5% in chemically treated and control cultures. Also the background rate which is a good indicator for the genetic stability of the cells seen in MN experiments in different laboratories were fairly stable (see Valentin-Severin et al (2003); Fatur et al (2002); Mersch-Sundermann et al (2001); Majer et al (2003). Fig.…”

Section: Possible Pitfalls and Problems Encountered In Genotoxicity Ementioning

confidence: 94%

Use of human-derived liver cell lines for the detection of environmental and dietary genotoxicants; current state of knowledge

et al. 2004

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Investigation of the genotoxic effects of 2-amino-9H-pyrido[2,3-b]indole in different organs of rodents and in human derived cells

Cited by 21 publications

References 40 publications

Metabolism of the Tobacco Carcinogen 2-Amino-9H-pyrido[2,3-b]indole (AαC) in Primary Human Hepatocytes

Metabolism of the Tobacco Carcinogen 2-Amino-9H-pyrido[2,3-b]indole (AαC) in Primary Human Hepatocytes

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

Use of human-derived liver cell lines for the detection of environmental and dietary genotoxicants; current state of knowledge

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