Increased endogenous N-nitrosamine and nitrate formation by induction of nitric oxide synthase in rats with acute hepatic injury caused by Propionibacterium acnes and lipopolysaccharide administration.
In rats treated i.v. with heat-killed Propionibacterium acnes (100 mg/kg body wt), followed 5 days later by an i.v. dose of Escherichia coli lipopolysaccharide (LPS, 1 mg/kg body wt), acute hepatic cell necrosis was accompanied by significant induction of nitric oxide (NO) synthase activity in the liver. Endogenous nitrosation of thiazolidine 4-carboxylic acid (TCA, 50 mumol/rat) administered by three different routes (i.v., i.p. and p.o.) 5 h after LPS injection to the P. acnes-treated rats was assessed by analysing its nitrosated product (NTCA) excreted in 24 h urine. The amounts of NTCA formed in vivo after i.v., i.p. and p.o. administration of TCA were 4.07 +/- 1.00, 5.79 +/- 2.15 and 58.3 +/- 20.7 nmol/rat (n = 5-10) respectively, which were about 5-, 10- and 8-fold greater than those excreted by rats which had not been treated with P.acnes and LPS but received TCA by the same route. Nitrate concentration in plasma and NO synthase activity in the liver started to increase within 2.5 h after LPS injection, reached a maximum at 7.5 h and remained at high levels for several further hours. Levels of nitrite and nitrate in gastric contents were also increased significantly after LPS administration. The co-administration of N omega-nitro-L-arginine (an inhibitor of NO synthase) and LPS resulted in a marked reduction of urinary levels of nitrate and NTCA, indicating that nitrosation is mediated by NO synthase. These results together suggest that induction of NO synthase by infection with bacteria, parasite and viruses could result in increased endogenous nitrosation not only in the infected tissues but also in the stomach, where nitrosamines would be formed more rapidly under acidic conditions.
Wu
Y
Y
Unit of Environmental Carcinogens and Host Factors, International Agency for Research on Cancer, Lyon, France.
Brouet
I
I
Calmels
S
S
Bartsch
H
H
Ohshima
H
H
D000594:Amino Acid Oxidoreductases / Q000096:biosynthesis* / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D004790:Enzyme Induction; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity*; D008107:Liver Diseases / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D008297:Male; D009336:Necrosis / Q000201:enzymology / Q000209:etiology; D009566:Nitrates / Q000097:blood / Q000378:metabolism* / Q000652:urine; D019001:Nitric Oxide Synthase; D009602:Nitrosamines / Q000378:metabolism*; D009603:Nitroso Compounds / Q000008:administration & dosage / Q000378:metabolism; D011425:Propionibacterium acnes; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000008:administration & dosage / Q000378:metabolism; D053778:Thiazolidines
D008070:Lipopolysaccharides; D009566:Nitrates; D009602:Nitrosamines; D009603:Nitroso Compounds; D013844:Thiazoles; D053778:Thiazolidines; C040387:N-nitrosothiazolidine-4-carboxylic acid; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases