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Protein tyrosine nitration and poly(ADP-ribose) polymerase activation in N-methyl-N-nitro-N-nitrosoguanidine-treated thymocytes: implication for cytotoxicity.
Toxicol Lett. 2007 May 15; 170(3):203-13.TL

Abstract

1-Methyl-3-nitro-1-nitrosoguanidine (MNNG) is a DNA alkylating agent. DNA alkylation by MNNG is known to trigger accelerated poly(ADP-ribose) metabolism. Various nitroso compounds release nitric oxide (NO). Therefore, we set out to investigate whether MNNG functions as NO donor and whether MNNG-derived NO or secondary NO metabolites such as peroxynitrite contribute to MNNG-induced cytotoxicity. MNNG in aqueous solutions resulted in time- and concentration-dependent NO release and nitrite/nitrate formation. Moreover, various proteins in MNNG-treated thymocytes were found to be nitrated, indicating that MNNG-derived NO may combine with cellular superoxide to form peroxynitrite, a nitrating agent. MNNG also caused DNA breakage and increased poly(ADP-ribose) polymerase activity and cytotoxicity in thymocytes. MNNG-induced DNA damage (measured by the comet assay) and thymocyte death (measured by propidium iodide uptake) was prevented by the PARP inhibitor PJ-34 and by glutathione (GSH) or N-acetylcysteine (NAC). The cytoprotection provided by PJ-34 against necrotic parameters was paralleled by increased outputs in apoptotic parameters (caspase activity, DNA laddering) indicating that PARP activation diverts apoptotic death toward necrosis. As MNNG-induced cytotoxicity showed many similarities to peroxynitrite-induced cell death, we tested whether peroxynitrite was responsible for at least part of the cytotoxicity induced by MNNG. Cell-permeable enzymic antioxidants (superoxide dismutase and catalase), the NO scavenger cPTIO or the peroxynitrite decomposition catalyst FP15 failed to inhibit MNNG-induced DNA breakage and cytotoxicity. In conclusion, MNNG induces tyrosine nitration in thymocytes. Furthermore, MNNG damages DNA by a radical mechanism that does not involve NO or peroxynitrite.

Authors+Show Affiliations

Department of Medical Chemistry, MHSC, RCMM, University of Debrecen, H-4032 Debrecen, Nagyerdei krt. 98, Hungary.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17428624

Citation

Bai, Péter, et al. "Protein Tyrosine Nitration and poly(ADP-ribose) Polymerase Activation in N-methyl-N-nitro-N-nitrosoguanidine-treated Thymocytes: Implication for Cytotoxicity." Toxicology Letters, vol. 170, no. 3, 2007, pp. 203-13.
Bai P, Hegedus C, Erdélyi K, et al. Protein tyrosine nitration and poly(ADP-ribose) polymerase activation in N-methyl-N-nitro-N-nitrosoguanidine-treated thymocytes: implication for cytotoxicity. Toxicol Lett. 2007;170(3):203-13.
Bai, P., Hegedus, C., Erdélyi, K., Szabó, E., Bakondi, E., Gergely, S., Szabó, C., & Virág, L. (2007). Protein tyrosine nitration and poly(ADP-ribose) polymerase activation in N-methyl-N-nitro-N-nitrosoguanidine-treated thymocytes: implication for cytotoxicity. Toxicology Letters, 170(3), 203-13.
Bai P, et al. Protein Tyrosine Nitration and poly(ADP-ribose) Polymerase Activation in N-methyl-N-nitro-N-nitrosoguanidine-treated Thymocytes: Implication for Cytotoxicity. Toxicol Lett. 2007 May 15;170(3):203-13. PubMed PMID: 17428624.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Protein tyrosine nitration and poly(ADP-ribose) polymerase activation in N-methyl-N-nitro-N-nitrosoguanidine-treated thymocytes: implication for cytotoxicity. AU - Bai,Péter, AU - Hegedus,Csaba, AU - Erdélyi,Katalin, AU - Szabó,Eva, AU - Bakondi,Edina, AU - Gergely,Szabolcs, AU - Szabó,Csaba, AU - Virág,László, Y1 - 2007/03/14/ PY - 2006/11/29/received PY - 2007/03/09/revised PY - 2007/03/12/accepted PY - 2007/4/13/pubmed PY - 2007/7/11/medline PY - 2007/4/13/entrez SP - 203 EP - 13 JF - Toxicology letters JO - Toxicol Lett VL - 170 IS - 3 N2 - 1-Methyl-3-nitro-1-nitrosoguanidine (MNNG) is a DNA alkylating agent. DNA alkylation by MNNG is known to trigger accelerated poly(ADP-ribose) metabolism. Various nitroso compounds release nitric oxide (NO). Therefore, we set out to investigate whether MNNG functions as NO donor and whether MNNG-derived NO or secondary NO metabolites such as peroxynitrite contribute to MNNG-induced cytotoxicity. MNNG in aqueous solutions resulted in time- and concentration-dependent NO release and nitrite/nitrate formation. Moreover, various proteins in MNNG-treated thymocytes were found to be nitrated, indicating that MNNG-derived NO may combine with cellular superoxide to form peroxynitrite, a nitrating agent. MNNG also caused DNA breakage and increased poly(ADP-ribose) polymerase activity and cytotoxicity in thymocytes. MNNG-induced DNA damage (measured by the comet assay) and thymocyte death (measured by propidium iodide uptake) was prevented by the PARP inhibitor PJ-34 and by glutathione (GSH) or N-acetylcysteine (NAC). The cytoprotection provided by PJ-34 against necrotic parameters was paralleled by increased outputs in apoptotic parameters (caspase activity, DNA laddering) indicating that PARP activation diverts apoptotic death toward necrosis. As MNNG-induced cytotoxicity showed many similarities to peroxynitrite-induced cell death, we tested whether peroxynitrite was responsible for at least part of the cytotoxicity induced by MNNG. Cell-permeable enzymic antioxidants (superoxide dismutase and catalase), the NO scavenger cPTIO or the peroxynitrite decomposition catalyst FP15 failed to inhibit MNNG-induced DNA breakage and cytotoxicity. In conclusion, MNNG induces tyrosine nitration in thymocytes. Furthermore, MNNG damages DNA by a radical mechanism that does not involve NO or peroxynitrite. SN - 0378-4274 UR - https://www.unboundmedicine.com/medline/citation/17428624/Protein_tyrosine_nitration_and_poly_ADP_ribose__polymerase_activation_in_N_methyl_N_nitro_N_nitrosoguanidine_treated_thymocytes:_implication_for_cytotoxicity_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-4274(07)00087-2 DB - PRIME DP - Unbound Medicine ER -