A mechanism of paraquat toxicity involving nitric oxide synthase.

Published

Journal Article

Paraquat (PQ) is a well described pneumotoxicant that produces toxicity by redox cycling with cellular diaphorases, thereby elevating intracellular levels of superoxide (O-(2)). NO synthase (NOS) has been shown to participate in PQ-induced lung injury. Current theory holds that NO reacts with O-(2) generated by PQ to produce the toxin peroxynitrite. We asked whether NOS might alternatively function as a PQ diaphorase and reexamined the question of whether NO/O-(2) reactions were toxic or protective. Here, we show that: (i) neuronal NOS has PQ diaphorase activity that inversely correlates with NO formation; (ii) PQ-induced endothelial cell toxicity is attenuated by inhibitors of NOS that prevent NADPH oxidation, but is not attenuated by those that do not; (iii) PQ inhibits endothelium-derived, but not NO-induced, relaxations of aortic rings; and (iv) PQ-induced cytotoxicity is potentiated in cytokine-activated macrophages in a manner that correlates with its ability to block NO formation. These data indicate that NOS is a PQ diaphorase and that toxicity of such redox-active compounds involves a loss of NO-related activity.

Full Text

Duke Authors

Cited Authors

  • Day, BJ; Patel, M; Calavetta, L; Chang, LY; Stamler, JS

Published Date

  • October 1999

Published In

Volume / Issue

  • 96 / 22

Start / End Page

  • 12760 - 12765

PubMed ID

  • 10535996

Pubmed Central ID

  • 10535996

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.96.22.12760

Language

  • eng