Hepatoprotective Limonoids from Andiroba (Carapa guianensis).
Three gedunin-type limonoids, gedunin (1), 6α-acetoxygedunin (2), and 7-deacetoxy-7-oxogedunin (3), which were isolated from the seed and flower oils of andiroba (Carapa guianensis Aublet, Meliaceae), exhibited hepatoprotective effects at doses of 25 mg/kg, p.o. against d-galactosamine (d-GalN)/lipopolysaccharide (LPS)-induced liver injury in mice. To characterize the mechanisms of action of 1-3 and clarify the structural requirements for their hepatoprotective effects, 17 related limonoids (1-17) isolated from the seed and/or flower oils of C. guianensis were examined in in vitro studies assessing their effects on (i) d-GalN-induced cytotoxicity in primary cultured mouse hepatocytes, (ii) LPS-induced nitric oxide (NO) production in mouse peritoneal macrophages, and (iii) tumor necrosis factor-α (TNF-α)-induced cytotoxicity in L929 cells. The mechanisms of action of 1-3 are likely to involve the inhibition of LPS-induced macrophage activation and reduced sensitivity of hepatocytes to TNF-α; however, these compounds did not decrease the cytotoxicity caused by d-GalN. In addition, the structural requirements of limonoids (1-17) for inhibition of LPS-induced NO production in mouse peritoneal macrophages and TNF-α-induced cytotoxicity in L929 cells were evaluated.
Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan. ninomiya@phar.kindai.ac.jp.|Antiaging Center, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan. ninomiya@phar.kindai.ac.jp.
Kiyofumi
K
Ninomiya
Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan. t0m0n1.aym-iv0.akrmn@ezweb.ne.jp.
Seiya
S
Miyazawa
Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan. kaiten.ozeki@gmail.com.
Kaiten
K
Ozeki
Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan. 1111610153n@kindai.ac.jp.
Natsuko
N
Matsuo
Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan. muraoka@phar.kindai.ac.jp.|Antiaging Center, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan. muraoka@phar.kindai.ac.jp.|Laboratory of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan. muraoka@phar.kindai.ac.jp.
Osamu
O
Muraoka
Laboratory of Medicinal Chemistry, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan. t.kikuchi@gly.oups.ac.jp.
Takashi
T
Kikuchi
Laboratory of Medicinal Chemistry, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan. yamada@gly.oups.ac.jp.
Takeshi
T
Yamada
Laboratory of Medicinal Chemistry, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan. tanakar@gly.oups.ac.jp.
Reiko
R
Tanaka
Pharmaceutical Research and Technology Institute, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan. morikawa@kindai.ac.jp.|Antiaging Center, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan. morikawa@kindai.ac.jp.
Toshio
T
Morikawa
D000818:Animals; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control; D035264:Flowers / Q000737:chemistry; D022781:Hepatocytes / Q000187:drug effects*; D036701:Limonins / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000187:drug effects; D008297:Male; D029582:Meliaceae / Q000737:chemistry*; D051379:Mice; D008815:Mice, Inbred Strains; D009569:Nitric Oxide / Q000378:metabolism; D012639:Seeds / Q000737:chemistry
D036701:Limonins; D008070:Lipopolysaccharides; D009569:Nitric Oxide
Carapa guianensis; Meliaceae; andiroba; hepatoprotective effect; limonoid; structural requirement