Nitric oxide synthase inhibition promotes carcinogen-induced preneoplastic changes in the colon of rats.
l-Arginine is metabolized either to polyamines through arginase and ornithine decarboxylase (ODC) activities or to citrulline and nitric oxide (NO, nitrogen monoxide) through the NO synthase (NOS) pathway. Polyamine levels and ODC activity are high in tumor cells. The aim of this study was to test whether N(G)-nitro-l-arginine methyl ester (l-NAME), an inhibitor of NOS, modulates colon carcinogenesis. Adult male Wistar rats were treated with azoxymethane (AOM, 15 mg/kg ip), a chemical carcinogen, once a week for 2 weeks. One week after the second injection the rats were randomly divided into two groups. One group (n = 8) received l-NAME (10 mg/kg body wt/day) in drinking water. The control group (n = 8) received tap water. After 5 weeks, the rats receiving l-NAME showed enhanced mean basal arterial blood pressure, decreased heart rate, and a significant decrease of the cGMP content in the colonic mucosa. In both groups, AOM induced the formation of colonic aberrant crypt foci (ACF). In l-NAME-treated rats, the number of ACF was higher than in controls by 47%. ODC activity was enhanced by 11-fold. S-Adenosyl-methionine-decarboxylase activity and putrescine concentration were significantly increased in the colonic mucosa of l-NAME-treated rats. The data suggest that l-NAME promotes carcinogen-induced preneoplastic changes in the colon by inhibiting NOS activity and by stimulating polyamine biosynthesis.
Schleiffer
R
R
ULP/CJF INSERM 95-09, Laboratoire du Contrôle Métabolique et Nutritionnel en Oncologie Digestive, IRCAD, 1, Place de l'Hôpital, 67091 Strasbourg-Cedex, France.
Duranton
B
B
Gossé
F
F
Bergmann
C
C
Raul
F
F
D012437:Adenosylmethionine Decarboxylase / Q000378:metabolism; D000818:Animals; D001397:Azoxymethane; D015317:Biogenic Polyamines / Q000096:biosynthesis; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens; D003106:Colon / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D006152:Cyclic GMP / Q000032:analysis / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D007413:Intestinal Mucosa / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009955:Ornithine Decarboxylase / Q000378:metabolism; D011230:Precancerous Conditions / Q000139:chemically induced / Q000201:enzymology*; D011700:Putrescine / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013095:Spermidine / Q000378:metabolism; D013096:Spermine / Q000378:metabolism
D015317:Biogenic Polyamines; D002273:Carcinogens; D004791:Enzyme Inhibitors; D013096:Spermine; D019001:Nitric Oxide Synthase; D009955:Ornithine Decarboxylase; D012437:Adenosylmethionine Decarboxylase; D006152:Cyclic GMP; D001397:Azoxymethane; D013095:Spermidine; D011700:Putrescine; D019331:NG-Nitroarginine Methyl Ester