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Nuclear DNA and Mitochondrial Damage of the Cooked Meat Carcinogen 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in Human Neuroblastoma Cells
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Nuclear DNA and Mitochondrial Damage of the Cooked Meat Carcinogen 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in Human Neuroblastoma Cells
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  • Medjda Bellamri
    Medjda Bellamri
    Masonic Cancer Center and Department of Medicinal Chemistry, Cancer and Cardiovascular Research Building, University of Minnesota, 2231 6th Street, Minneapolis, Minnesota 55455, United States
    More by Medjda Bellamri
    Orcidhttps://orcid.org/0000-0002-6477-967X
  • Kyle Brandt
    Kyle Brandt
    Masonic Cancer Center and Department of Medicinal Chemistry, Cancer and Cardiovascular Research Building, University of Minnesota, 2231 6th Street, Minneapolis, Minnesota 55455, United States
    More by Kyle Brandt
    Orcidhttps://orcid.org/0000-0002-7038-5917
  • Kari Cammerrer
    Kari Cammerrer
    Masonic Cancer Center and Department of Medicinal Chemistry, Cancer and Cardiovascular Research Building, University of Minnesota, 2231 6th Street, Minneapolis, Minnesota 55455, United States
    More by Kari Cammerrer
  • Tauqeerunnisa Syeda
    Tauqeerunnisa Syeda
    School of Health Sciences, Purdue Institute for Integrative Neurosciences, Purdue University, West Lafayette, Indiana 47907, United States
    Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, Indiana 47907, United States
    More by Tauqeerunnisa Syeda
  • Robert J. Turesky*
    Robert J. Turesky
    Masonic Cancer Center and Department of Medicinal Chemistry, Cancer and Cardiovascular Research Building, University of Minnesota, 2231 6th Street, Minneapolis, Minnesota 55455, United States
    *Email: [email protected]
    More by Robert J. Turesky
    Orcidhttps://orcid.org/0000-0001-7355-9903
  • Jason R. Cannon*
    Jason R. Cannon
    School of Health Sciences, Purdue Institute for Integrative Neurosciences, Purdue University, West Lafayette, Indiana 47907, United States
    Purdue Institute for Integrative Neuroscience, Purdue University, West Lafayette, Indiana 47907, United States
    *Email: [email protected]
    More by Jason R. Cannon
    Orcidhttps://orcid.org/0000-0003-1907-4555
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Chemical Research in Toxicology

Cite this: Chem. Res. Toxicol. 2023, 36, 8, 1361–1373
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https://doi.org/10.1021/acs.chemrestox.3c00109
Published July 8, 2023
Copyright © 2023 American Chemical Society
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Abstract

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Animal fat and iron-rich diets are risk factors for Parkinson’s disease (PD). The heterocyclic aromatic amines (HAAs) harman and norharman are neurotoxicants formed in many foods and beverages, including cooked meats, suggesting a role for red meat in PD. The structurally related carcinogenic HAAs 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-3,8-dimethylmidazo[4,5-f]quinoxaline (MeIQx), and 2-amino-9H-pyrido[2,3-b]indole (AαC) also form in cooked meats. We investigated the cytotoxicity, DNA-damaging potential, and mitochondrial damage of HAAs and their genotoxic HONH-HAA metabolites in galactose-dependent SH-SY5Y cells, a human neuroblastoma cell line relevant for PD-related neurotoxicity. All HAAs and HONH-HAAs induced weak toxicity except HONH-PhIP, which was 1000-fold more potent than the other chemicals. HONH-PhIP DNA adduct formation occurred at 300-fold higher levels than adducts formed with HONH-MeIQx and HONH-AαC, assuming similar cellular uptake rates. PhIP-DNA adduct levels occurred at concentrations as low as 1 nM and were threefold or higher and more persistent in mitochondrial DNA than nuclear DNA. N-Acetyltransferases (NATs), sulfotransferases, and kinases catalyzed PhIP-DNA binding and converted HONH-PhIP to highly reactive ester intermediates. DNA binding assays with cytosolic, mitochondrial, and nuclear fractions of SH-SY5Y fortified with cofactors revealed that cytosolic AcCoA-dependent enzymes, including NAT1, mainly carried out HONH-PhIP bioactivation to form N-acetoxy-PhIP, which binds to DNA. Furthermore, HONH-PHIP and N-acetoxy-PhIP inhibited mitochondrial complex-I, -II, and -III activities in isolated SH-SY5Y mitochondria. Mitochondrial respiratory chain complex dysfunction and DNA damage are major mechanisms in PD pathogenesis. Our data support the possible role of PhIP in PD etiology.

Copyright © 2023 American Chemical Society

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Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.chemrestox.3c00109.

  • UPLC-ESI/MS3 chromatograms and MS3 scan ion spectra of AαC, MeIQx, and PhIP DNA adducts formed in SH-SY5Y cells and UPLC-ESI/MS2 chromatograms and MS2 scan ion spectra of O6-MedG formed in SH-SY5Y cells treated MAM (PDF)

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Cited By

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This article is cited by 10 publications.

  1. Scott J. Walmsley, Jingshu Guo, Anamary Tarifa, Anthony P. DeCaprio, Marcus S. Cooke, Robert J. Turesky, Peter W. Villalta. Mass Spectral Library for DNA Adductomics. Chemical Research in Toxicology 2024, 37 (2) , 302-310. https://doi.org/10.1021/acs.chemrestox.3c00302
  2. Pengcheng Wang, Chen Wang, Yinsheng Wang. Nucleotide salvage, genome instability, and potential therapeutic applications. Nucleic Acids Research 2026, 54 (4) https://doi.org/10.1093/nar/gkag099
  3. Yelena Oleinikova, Sviatoslav Maksimovich, Irina Khadzhibayeva, Elana Khamedova, Aizada Zhaksylyk, Aigul Alybayeva. Meat quality, safety, dietetics, environmental impact, and alternatives now and ten years ago: a critical review and perspective. Food Production, Processing and Nutrition 2025, 7 (1) https://doi.org/10.1186/s43014-024-00305-w
  4. Ke-qian Chen, Wen-jin Cao, Zheng Liu, Ren-zhu Liu. Mini-review: Processed red meat intake and risk of neurodegenerative diseases. Frontiers in Nutrition 2025, 12 https://doi.org/10.3389/fnut.2025.1663647
  5. Chao Ma, Huiqin Zhang, Ziwei Liu, Xinran Meng, Sijia Chen, Jingsong Zhang, Yeqiang Li, Xia Huang. Treatment options of nitrogen heterocyclic compounds in industrial wastewater: From fundamental technologies to energy valorization applications and future process design strategies. Water Research 2025, 281 , 123575. https://doi.org/10.1016/j.watres.2025.123575
  6. Fatema Currim, Jason Cannon. Mitochondrial toxicants to model Parkinson’s disease. 2025, 141-197. https://doi.org/10.1016/bs.ant.2025.02.005
  7. Mantong Zhao, Zhongyuan Liu, Mengyin Zha, Ying Sun, Haohao Shi, Xueying Zhang, Chuan Li, Guanghua Xia. Investigation of the dose and structure effects of lipid oxidation products aldehydes on the generation of heterocyclic amines: A case study of 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP). Food Chemistry: X 2025, 25 , 102244. https://doi.org/10.1016/j.fochx.2025.102244
  8. Chun-Han Chang, Pei-Ling Yen, Min-Hsiung Pan, Vivian Hsiu-Chuan Liao. The food-borne carcinogenic 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) disrupts circadian rhythms and ameliorated by pterostilbene (PSB) in Caenorhabditis elegans. Archives of Toxicology 2024, 98 (12) , 4131-4141. https://doi.org/10.1007/s00204-024-03857-5
  9. Arumugam Vignesh, Thomas Cheeran Amal, Krishnan Vasanth. Food contaminants: Impact of food processing, challenges and mitigation strategies for food security. Food Research International 2024, 191 , 114739. https://doi.org/10.1016/j.foodres.2024.114739
  10. . Understanding the heterocyclic aromatic amines: An overview and recent findings. 2024, 1-66. https://doi.org/10.1016/bs.afnr.2024.02.002
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Chemical Research in Toxicology

Cite this: Chem. Res. Toxicol. 2023, 36, 8, 1361–1373
Click to copy citationCitation copied!
https://doi.org/10.1021/acs.chemrestox.3c00109
Published July 8, 2023
Copyright © 2023 American Chemical Society
Request reuse permissions

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