Hepatoprotective effects of flavonoids from shekwasha (Citrus depressa) against D-galactosamine-induced liver injury in rats.
We attempted to isolate the constituent(s) responsible for the suppressive effect of the juice of shekwasha, a citrus produced in Okinawa Prefecture, on D-galactosamine (GalN)-induced liver injury in rats. Liver injury-suppressive activity, as assessed by plasma alanine aminotransferase and aspartate aminotransferase activities, was found only in the fraction that was extracted with n-hexane when three fractions were added to the diet and fed to rats. Of five compounds isolated from the n-hexane-soluble fraction by silica gel column chromatography, three compounds had liver injury-suppressive effects when five compounds were singly force-fed to rats at a level of 300 mg/kg body wt 4 h before the injection with GalN. The structures of the three active compounds were determined as 3',4',5,6,7,8-hexamethoxyflavanone (citromitin), 4',5,6,7,8-pentamethoxyflavone (tangeretin) and 3',4',5,6,7,8-hexamethoxyflavone (nobiletin), which are known flavonoids mainly existing in citrus. Nobiletin, the most important compound in the n-hexane-soluble fraction, also had suppressive effects on liver injuries induced by carbon tetrachloride, acetaminophen and GalN/lipopolysaccharide (LPS) in addition to liver injury induced GalN. Nobiletin suppressed GalN/LPS-induced increases in plasma tumor necrosis factor (TNF)-alpha and nitric oxide (NO) concentrations and hepatic mRNA levels for inducible NO synthase and DNA fragmentation. These results suggest that nobiletin suppressed GalN/LPS-induced liver injury at least by suppressing the production of both TNF-alpha and NO. The results obtained here indicate that the hepatoprotective effect of shekwasha juice is mainly ascribed to several polymethoxy flavonoids included in the juice.
Akachi
Toshiyuki
T
The United Graduate School of Agricultural Science, Gifu University, Gifu, Japan. acksugi@agr.shizuoka.ac.jp
Shiina
Yasuyuki
Y
Ohishi
Yayoi
Y
Kawaguchi
Takumi
T
Kawagishi
Hirokazu
H
Morita
Tatsuya
T
Mori
Makoto
M
Sugiyama
Kimio
K
D000082:Acetaminophen; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002252:Carbon Tetrachloride Poisoning / Q000188:drug therapy; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy*; D002957:Citrus / Q000737:chemistry*; D053938:DNA Fragmentation / Q000187:drug effects; D047309:Flavones / Q000494:pharmacology / Q000627:therapeutic use*; D005419:Flavonoids / Q000494:pharmacology / Q000627:therapeutic use*; D005688:Galactosamine; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D015394:Molecular Structure; D009569:Nitric Oxide / Q000097:blood; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D008517:Phytotherapy; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D047309:Flavones; D005419:Flavonoids; D008070:Lipopolysaccharides; D010936:Plant Extracts; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D000082:Acetaminophen; D005688:Galactosamine; C008661:nobiletin; D052247:Nitric Oxide Synthase Type II; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase