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Tytuł:
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Genotoxic effects of 1-nitropyrene in macrophages are mediated through a p53-dependent pathway involving cytochrome c release, caspase activation, and PARP-1 cleavage.
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Autorzy:
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Wu SW; Division of Nephrology, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan; The School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
Su CH; Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan; Department of Internal Medicine, School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
Ho YC; School of Medical Applied Chemistry, Chung Shan Medical University, Taichung, Taiwan.
Huang-Liu R; School of Nutrition, Chung Shan Medical University, Taichung, Taiwan.
Tseng CC; Aerospace Center Hospital, Peking University, Beijing, China.
Chiang YW; Department of life sciences, National Chung-Hsing University, Taichung, Taiwan.
Yeh KL; Department of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan.
Lee SS; School of Public Health, Chung Shan Medical University, Taichung, Taiwan.
Chen WY; Department of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan.
Chen CJ; Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan.
Li YC; Department of Pharmacology, School of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Pharmacy, Chung Shan Medical University Hospital, Taichung, Taiwan.
Lee CY; Department of Pharmacology, School of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Pharmacy, Chung Shan Medical University Hospital, Taichung, Taiwan.
Kuan YH; Department of Pharmacology, School of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Pharmacy, Chung Shan Medical University Hospital, Taichung, Taiwan. Electronic address: .
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Źródło:
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Ecotoxicology and environmental safety [Ecotoxicol Environ Saf] 2021 Apr 15; Vol. 213, pp. 112062. Date of Electronic Publication: 2021 Feb 20.
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Typ publikacji:
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Journal Article
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Język:
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English
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Imprint Name(s):
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Original Publication: Amsterdam, Netherlands : Elsevier
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MeSH Terms:
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Caspases/*metabolism
Poly (ADP-Ribose) Polymerase-1/*metabolism
Pyrenes/*toxicity
Apoptosis/drug effects ; Caspase 9/metabolism ; Cytochromes c/metabolism ; DNA Damage ; Humans ; Macrophages/metabolism ; Mitochondria/drug effects ; Phosphorylation/drug effects ; Poly(ADP-ribose) Polymerase Inhibitors/metabolism ; Tumor Suppressor Protein p53/metabolism
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Contributed Indexing:
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Keywords: 1-Nitropyrene; Genotoxicity; Macrophage; p53-dependent pathway
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Substance Nomenclature:
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0 (Poly(ADP-ribose) Polymerase Inhibitors)
0 (Pyrenes)
0 (Tumor Suppressor Protein p53)
9007-43-6 (Cytochromes c)
EC 2.4.2.30 (Poly (ADP-Ribose) Polymerase-1)
EC 3.4.22.- (Caspase 9)
EC 3.4.22.- (Caspases)
TD1665I8Q4 (1-nitropyrene)
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Entry Date(s):
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Date Created: 20210222 Date Completed: 20210318 Latest Revision: 20210318
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Update Code:
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20240105
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DOI:
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10.1016/j.ecoenv.2021.112062
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PMID:
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33618169
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Genotoxic stress from environmental pollutants plays a critical role in cytotoxicity. The most abundant nitro-polycyclic aromatic hydrocarbon in environmental pollutants, 1-nitropyrene (1-NP), is generated during fossil fuel, diesel, and biomass combustion under sunlight. Macrophages, the key regulators of the innate immune system, provide the first line of defense against pathogens. The toxic effects of 1-NP on macrophages remain unclear. Through a lactate dehydrogenase assay, we measured the cytotoxicity induced by 1-NP. Our results revealed that 1-NP induced genotoxicity also named DNA damage, including micronucleus formation and DNA strand breaks, in a concentration-dependent manner. Furthermore, 1-NP induced p53 phosphorylation and nuclear accumulation; mitochondrial cytochrome c release; caspase-3 and -9 activation and cleavage; and poly (ADP-ribose) polymerase-1 (PARP-1) cleavage in a concentration-dependent manner. Pretreatment with the PARP inhibitor, 3-aminobenzamide, significantly reduced cytotoxicity, genotoxicity, and PARP-1 cleavage induced by 1-NP. Pretreatment with the caspase-3 inhibitor, z-DEVD-fmk, significantly reduced cytotoxicity, genotoxicity, PARP-1 cleavage, and caspase 3 activation induced by 1-NP. Pretreatment with the p53 inhibitor, pifithrin-α, significantly reduced cytotoxicity, genotoxicity, PARP-1 cleavage, caspase 3 activation, and p53 phosphorylation induced by 1-NP. We propose that cytotoxicity and genotoxicity induced by 1-NP by PARP-1 cleavage via caspase-3 and -9 activation through cytochrome c release from mitochondria and its upstream p53-dependent pathway in macrophages.
(Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
