NITRIC OXIDE: Biology and Chemistry Vol. 1, No. 3, June, pp. 268–272 (1997) Article No. NO970127 BRIEF COMMUNICATION Polyamines Inhibit Lipopolysaccharide-Induced Nitric Oxide Synthase Activity in Rat Liver Cytosol Franc ¸ois Blachier,* Alexandre Mignon,² and Olivier Soubrane‡ *Unite ´ d’Ecologie et de Physiologie du Syste `me Digestif, Ba ˆ timent 405, Institut National de la Recherche Agronomique, 78352 Jouy-en-Josas, France; ²Institut National de la Sante ´ et de la Recherche Me ´dicale, Faculte ´ de Me ´decine Cochin, Port Royal 24, rue du Faubourg Saint Jacques, U-129, 75014 Paris, France; and ‡Laboratoire de recherche chirurgicale, Ho ˆpital Cochin, 27, rue du Faubourg Saint Jacques, 75014 Paris, France Received February 26, 1997, and in revised form April 16, 1997 untreated rats (1). This basal NO production can be Liver cells can produce nitric oxide from L-argi- spectacularly increased in hepatocytes or Kupffer nine through either constitutive NO synthase or in- cells by in vivo or in vitro treatment with a combina- ducible NO synthase (NOS) detected after in vivo or tion of cytokines and/or lipopolysaccharide (LPS) in vitro treatment with cytokines and/or lipopoly- (2–7). Although NO can exert a beneficial effect (8– saccharide (LPS). The effects of NO on liver cells 11), it has been proposed that when NO is produced are associated with protein synthesis and mitochon- in excess it might be deleterious for liver physiology drial electron transfer inhibition. L-Arginine is also (6). To support this hypothesis, NO has been shown the precursor of L-ornithine and polyamines. The to decrease protein synthesis (7, 12), mitochondrial latter are considered to be protective in the liver in electron transfer (13, 14), and hepatocyte growth several experimental models. The aim of the present (6). NO is even able to severely affect hepatocyte work was to test the effects of polyamines on LPS- inducible NOS activity in rat liver cytosol using the viability by mobilizing mitochondrial calcium (15). test of radioactive L-citrulline synthesis from L-[gu- In contrast, polyamines have been shown to be pro- anido- 14 C]arginine. The three polyamines inhibited tective in several models of hepatic injury (16, 17). inducible NO synthase activity with the following In the liver, polyamines which are derived from L- hierarchy: spermine ú spermidine É putrescine. ornithine (a metabolite derived from L-arginine) are The 0.5 mM spermine was found to inhibit 50% of involved in hepatic protein synthesis (16). L-Argi- inducible NO synthase activity. The present data nine is taken up by hepatocytes through a low-affin- suggest an inhibitory interrelationship in the liver ity and high-capacity transporter (18) and then de- between two metabolites derived from the common graded by the highest arginase activity ever re- precursor L-arginine. q 1997 Academic Press ported in mammalian cells into L-ornithine and urea (19). L-Ornithine is the substrate for liver ornithine decarboxylase and allows putrescine synthesis (20). Synthesis of NO by constitutive NO synthase The presence of S-adenosylmethionine decarboxyl- (NOS) 1 has been shown in hepatocytes isolated from ase activity in the liver which is necessary for the synthesis of decarboxylated S-adenosylmethionine, 1 Abbreviations used: NOS, nitric oxide synthase; LPS, lipopoly- the cosubstrate for spermidine and spermine pro- saccharide; BH 4 , 6-(R,S)-5,6,7,8-tetrahydro-L-biopterin; cNOS, constitutive NOS; iNOS, inducible NOS. duction (21), suggests that the liver is able to synthe- 268 1089-8603/97 $25.00 Copyright q 1997 by Academic Press All rights of reproduction in any form reserved.