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L-arginine increases UVA cytotoxicity in irradiated human keratinocyte cell line: potential role of nitric oxide

CHRISTINE DIDIER^*, NATHALIE EMONET-PICCARDI^*, JEAN-CLAUDE BéANI^*, JEAN CADET and MARIE-JEANNE RICHARD^*1

^* LBSO/LCR7 No. 8-Université Joseph Fourier, F-38043 Grenoble Cedex 03, France; and
`Laboratoire Lésions des Acides Nucléiques', Département de Recherche Fondamentale sur la Matière Condensée, Service de Chimie Inorganique et Biologie, CEA/Grenoble, F-38054 Grenoble Cedex 9, France

¹Correspondence: LBSO, Laboratoire de Biochimie C, C. H. U. Albert Michallon, 38043 Grenoble Cedex 03, France. E-mail:

Human fibroblasts and keratinocytes possess nitric oxide synthases (NOS), which metabolize L-arginine (L-Arg) for producing nitric oxide (NO^•). This report delineates the relations between NO^• and UVA in the human keratinocyte cell line HaCaT. NOS activity was stimulated by exposure of cells to L-Arg just after irradiation. L-Arg (5 mM) supply led to an increase in UVA (25.3 J/cm²) cytotoxicity (% of viability 18 ± 3%) whereas neither L-Arg itself nor UVA irradiation induced cell death at the doses used in this study. Cells were also treated either with L-thiocitrulline (L-Thio), an irreversible inhibitor of NOS, or with exogenous superoxide dismutase (SOD) and catalase. L-Thio and SOD prevented L-Arg-mediated deleterious effects in irradiated cells, whereas catalase was ineffective. Intracellular antioxidant enzyme activities were also determined. UVA/L-Arg stress altered catalase (66% decrease) and glutathione peroxidase (83% decrease). DNA damage was evaluated using the `comet assay' and quantified using the `tail moment'. UVA alone was genotoxic (mean tail moment: 25.43 ± 1.23, P<0.001 compared control cells). The addition of L-Arg potentiated DNA damage (mean tail moment: 41.05±3.9) whereas L-Thio prevented them (mean tail moment 9.86 ± 0.98). We attempted to assess the effect of poly(ADP-ribose) polymerase (PARP) inhibition on cell death. Using the PARP inhibitor 3-aminobenzamide, we established that PARP determines both cell lysis and DNA damage induced by UVA and/or L-Arg. Our findings demonstrated that L-Arg was able to increase UVA-mediated deleterious effects in keratinocytes (both DNA damage and cytotoxicity) and that the ratio NO^•/O₂^•- plays a key role in these processes.—Didier, C., Emonet-Piccardi, N., Béani, J.-C., Cadet, J., Richard, M.-J. L-arginine increases UVA cytotoxicity in irradiated human keratinocyte cell line: potential role of nitric oxide.

Key Words: DNA damage • NO • metalloenzymes • SNAP

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