Nitric oxide. A macrophage product responsible for cytostasis and respiratory inhibition in tumor target cells.
A metabolic pathway of activated macrophages (M phi) involving oxidation of the guanido nitrogens of L-arginine is required for inhibition of growth and respiration of some target cells. The goal of this study was to identify the M phi metabolite(s) that induce these injuries. The stable products of the L-arginine pathway, NO2- and NO3-, were incapable of causing cytostasis under coculture conditions. However, NO2- became cytostatic upon mild acidification, which favors its transformation into nitrogen oxides of greater reactivity. This suggested that NO. (and/or NO2), recently identified as an M phi metabolite of L-arginine, could be a mediator. Authentic NO. caused cytostasis and respiratory inhibition in L1210 cells in a dose-dependent manner. The mitochondrial lesions caused by NO. were confined to complex 1 and 2, a pattern of injury identical to that seen after coculture with activated M phi. Inclusion of NO. scavenger systems prevented cytostasis from developing in M phi-L1210 cocultures. Thus, M phi-generated NO. can account for L-arginine-dependent cytostasis and respiratory inhibition.
Stuehr
D J
DJ
Beatrice and Samuel A. Seaver Laboratory, Department of Medicine, Cornell University Medical College, New York, New York 10021.
Nathan
C F
CF
D000818:Animals; D001120:Arginine / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D005609:Free Radicals; D007371:Interferon-gamma / Q000494:pharmacology; D007939:Leukemia L1210 / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D009211:Myoglobin / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism* / Q000494:pharmacology; D009585:Nitrogen Dioxide / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects
D005609:Free Radicals; D008070:Lipopolysaccharides; D009211:Myoglobin; D009566:Nitrates; D009569:Nitric Oxide; D007371:Interferon-gamma; D004247:DNA; D001120:Arginine; D009585:Nitrogen Dioxide