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J.Health Sci., 49(2), 160-165, 2003
Site-Specific Induction of Metallothionein in
N-Nitrosodimethylamine-Treated Rat Liver
Akira Yasutake,*, a Akinori
Shimada,b Yusuke
Mizutani,b and Misako
Taniguchic
aBiochemistry Section, National Institute for Minamata Disease, 4058-18 Hama, Minamata, Kumamoto 867-0008, Japan,
bDepartment of Veterinary Pathology, Tottori University, 4-101 Koyamacho-minami, Tottori 680-0945, Japan, and cDivision of
Food and Nutrition, Nakamura Gakuen University, 5-7-1 Jonan-ku, Fukuoka 814-0198, Japan
The effects of dietary protein and sulfur-containing amino acids on oxidative responses against
N-nitrosodimethylamine (NDMA) treatment were investigated in rat liver, focusing on the mechanism of
metallothionein (MT) induction. Rats were fed a 10% soybean protein isolate (SPI) diet or SPI supplemented
with 0.3% l-methionine (SPI-Met) for 3 weeks after weaning. Rats fed on SPI showed lower glutathione (GSH)
levels and higher MT levels in the liver than those fed on SPI-Met. After treatment with NDMA (20 mg/kg, i.p.),
MT levels were elevated significantly in both groups, whereas GSH levels were only elevated in the SPI group.
Pathologically, necrosis and hemorrhage were seen in the livers of NDMA-treated rats of both dietary groups,
suggesting oxidative damage caused by NDMA treatment. Immunological histochemistry using anti-MT
antibody showed that most of the MT was distributed in the cytosol region of all the rat groups. The ratios of the
MT-positive cells were correlated to MT levels that were chemically analyzed. It was notable that the
localization of MT staining in the hepatic lobules was altered after NDMA injection. The MT staining was principally
observed around the central vein before injection, whereas it was more markedly observed at the peripheral
region after NDMA treatment. These results indicate that the synthesis of hepatic MT basically occurs around
the central vein with oxygen stress caused by insufficient oxygen supplement and/or stimulated oxygen
consumption. NDMA could be oxidatively metabolized at the peripheral region with sufficient supplemental
oxygen from the artery, resulting in oxidative stress and stimulation of MT synthesis there. Thus, distribution of
tissue MT might vary depending on the site of oxidative stress.
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