Hepatoprotective Limonoids from Andiroba (Carapa guianensis)
Abstract
:1. Introduction
2. Results and Discussion
2.1. Isolation
2.2. Protective Effects of Principal Limonoids (1, 2, and 3) on Liver Injury Induced by d-GalN/LPS in Mice
2.3. Effects on d-GalN-induced Cytotoxicity in Primary Cultured Mouse Hepatocytes
2.4. Effects on LPS-induced NO Production in Mouse Peritoneal Macrophages
2.5. Effects on TNF-α-induced Cytotoxicity in L929 Cells
3. Materials and Methods
3.1. General Experimental Procedures
3.2. Material
3.3. Isolation of Compounds 1–3 from the Seed Oil of C. Guianensis
3.4. Reagents
3.5. Animals
3.6. Effects on d-GalN/LPS-induced Liver Injury in Mice
3.7. Effects on Cytotoxicity Induced by d-GalN in Primary Cultured Mouse Hepatocytes
3.8. Effects on Production of NO in LPS-induced Mouse Peritoneal Macrophages
3.9. Effects on Cytotoxicity Induced by TNF-α in L929 Cells
3.10. Statistics
4. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Treatment | Dose (mg/kg, p.o.) | N | sAST | sALT | Mortality | ||
---|---|---|---|---|---|---|---|
(Karmen Unit) | Inhibition (%) | (Karmen Unit) | Inhibition (%) | ||||
Normal (vehicle) | – | 8 | 107 ± 9 ** | – | 20 ± 2 ** | – | 0/8 |
Control | – | 12 | 5237 ± 1,000 | – | 8533 ± 1795 | – | 4/16 |
Gedunin (1) | 25 | 7 | 2304 ± 651 * | 56.2 | 2950 ± 710 * | 65.7 | 0/7 |
50 | 7 | 1923 ± 576 * | 63.5 | 2824 ± 754 * | 67.2 | 0/7 | |
6α-Acetoxygedunin (2) | 25 | 7 | 2384 ± 579 * | 54.7 | 3120 ± 830 * | 63.7 | 0/7 |
50 | 7 | 1696 ± 580 ** | 67.9 | 2397 ± 873 ** | 72.2 | 0/7 | |
7-Deacetoxy-7-oxo- | 25 | 7 | 2093 ± 742 * | 60.3 | 2899 ± 1024 * | 66.3 | 0/7 |
gedunin (3) | 50 | 6 | 1759 ± 579 * | 66.7 | 2572 ± 903 ** | 70.2 | 1/7 |
Control | – | 10 | 6033 ± 1647 | – | 6605 ± 1985 | – | 6/16 |
Curcumin [36] | 12.5 | 10 | 4770 ± 1218 | 21.1 | 5024 ± 1189 | 24.0 | 0/10 |
25 | 10 | 3177 ± 979 | 47.8 | 3253 ± 981 | 50.9 | 0/10 | |
50 | 9 | 2220 ± 563 * | 63.8 | 1916 ± 483 * | 71.2 | 1/10 | |
Control | – | 10 | 4709 ± 461 | – | 7088 ± 917 | – | 4/14 |
Silybin | 500 | 8 | 1361 ± 191 ** | 71.1 | 1990 ± 439 ** | 71.9 | 0/8 |
Treatment | Inhibition (%) | ||||
---|---|---|---|---|---|
0 µM | 3 µM | 10 µM | 30 µM | 100 µM | |
Gedunin (1) | 0.0 ± 1.8 | −8.4 ± 1.9 | −3.9 ± 0.4 | −3.2 ± 0.9 | −5.2 ±0.2 |
6α-Acetoxygedunin (2) | 0.0 ± 2.4 | −2.6 ± 1.0 | −1.9 ± 0.3 | −2.5 ± 0.7 | −1.8 ± 0.6 |
7-Deacetoxy-7-oxogedunin (3) | 0.0 ± 2.2 | −4.6 ± 0.5 | −8.2 ± 0.9 | −8.3 ± 1.1 | −8.9 ± 0.6 |
7-Deacetoxy-7α-hydroxygedunin (4) | 0.0 ± 1.6 | −2.0 ± 1.4 | −6.3 ± 0.5 | −8.0 ± 0.4 | −4.1 ± 0.7 |
Andirolide H (5) | 0.0 ± 2.5 | −6.2 ± 2.6 | −9.0 ± 0.5 | −9.2 ± 0.8 | −0.6 ± 0.8 |
6α-Hydroxygedunin (6) | 0.0 ± 2.0 | −7.2 ± 2.4 | −9.4 ± 0.8 | −0.1 ± 0.7 | −2.8 ± 0.5 |
Methyl angolensate (7) | 0.0 ± 2.2 | −2.1 ± 1.2 | −7.5 ± 0.9 | −6.3 ± 0.7 | −6.6 ± 1.0 |
Epoxyazadiradione (8) | 0.0 ± 2.1 | −3.1 ± 8.9 | −2.2 ± 2.5 | −10.8 ± 0.6 | −11.9 ± 0.3 |
17β-Hydroxyazadiradione (9) | 0.0 ± 2.0 | 15.3 ± 2.3 | −4.1 ± 1.2 | −7.5 ± 1.4 | −7.5 ± 4.0 |
Carapanolide C (10) | 0.0 ± 1.4 | 8.0 ± 4.3 | 3.4 ± 4.2 | 6.7 ± 2.1 | −7.7 ± 4.4 |
Carapanolide R (11) | 0.0 ± 2.1 | 21.5 ± 2.8 ** | 27.8 ± 5.0 ** | 46.0 ± 4.7 ** | 36.0 ± 3.2 ** |
Carapanolide S (12) | 0.0 ± 2.1 | −7.8 ± 3.2 | −3.8 ± 4.1 | −3.7 ± 3.1 | −7.1 ± 3.2 |
Carapanolide M (13) | 0.0 ± 1.6 | −7.0 ± 0.5 | −7.3 ± 0.7 | 1.0 ± 0.4 | −9.9 ± 1.0 |
Carapanolide Q (14) | 0.0 ± 1.6 | 2.7 ± 1.9 | −3.5 ± 2.9 | −2.5 ± 2.1 | −6.2 ± 1.7 |
Carapanolide O (15) | 0.0 ± 1.9 | 7.5 ± 3.9 | −5.3 ± 5.6 | −5.2 ± 3.9 | −2.1 ± 1.7 |
Guianolide A (16) | 0.0 ± 3.7 | 9.2 ± 4.2 | 11.0 ± 5.3 | 9.8 ± 2.8 | 23.5 ± 3.5 ** |
Carapanolide A (17) | 0.0 ± 2.0 | −6.8 ± 1.2 | −8.3 ± 0.7 | −4.5 ± 0.6 | −7.0 ± 0.6 |
Curcumin [26,27,29] | 0.0 ± 3.7 | 0.1 ± 3.8 | 1.1 ± 2.2 | −17.7 ± 1.3 | −44.3 ± 0.3 |
Silybin [33,35,36] | 0.0 ± 0.3 | 4.8 ± 1.1 | 7.7 ± 0.7 | 45.2 ± 8.8 ** | 77.0 ± 5.5 ** |
Treatment | Inhibition (%) | IC50 | ||||
---|---|---|---|---|---|---|
0 µM | 3 µM | 10 µM | 30 µM | 100 µM | (µM) | |
Gedunin (1) [17] | 0.0 ± 5.6 (100.0 ± 4.1) | 25.1 ± 2.5 ** (102.2 ± 5.3) | 84.5 ± 2.3 ** (119.5 ± 5.3) | 101.8 ± 0.6 ** (94.8 ± 1.4) | 100.9 ± 0.4 ** (3.0 ± 0.4 #) | 4.6 |
6α-Acetoxygedunin (2) [17] | 0.0 ± 1.5 (100.0 ± 1.6) | 16.9 ± 1.7 ** (96.8 ± 1.2) | 67.6 ± 4.6 ** (102.3 ± 2.2) | 88.4 ± 3.5 ** (92.5 ± 1.7) | 99.6 ± 0.2 ** (53.6 ± 5.1 #) | 7.9 |
7-Deacetoxy-7-oxogedunin (3) [17] | 0.0 ± 6.5 (100.0 ± 5.1) | 7.4 ± 5.2 (100.3 ± 3.9) | 40.9 ± 4.7 ** (98.9 ± 3.2) | 94.0 ± 0.8 ** (98.8 ± 7.4) | 88.1 ± 2.1 ** (83.7 ± 1.2) | 12.8 |
7-Deacetoxy-7α-hydroxy-gedunin (4) [17] | 0.0 ± 2.4 (100.0 ± 4.4) | 15.7 ± 4.6 ** (110.3 ± 5.9) | 55.7 ± 4.0 ** (106.6 ± 3.1) | 98.8 ± 0.4 ** (96.3 ± 4.6) | 100.2 ± 0.2 ** (2.6 ± 0.5 #) | 8.7 |
Andirolide H (5) | 0.0 ± 5.6 (100.0 ± 1.8) | 5.8 ± 6.1 (99.8 ± 4.5) | 63.9 ± 3.0 ** (103.9 ± 6.9) | 97.2 ± 0.9 ** (108.9 ± 2.4) | 99.7 ± 0.5 ** (4.9 ± 0.5 #) | 9.4 |
6α-Hydroxygedunin (6) [17] | 0.0 ± 6.2 (100.0 ± 4.5) | 7.7 ± 7.1 (88.4 ± 3.0) | 20.7 ± 4.3 ** (87.6 ± 4.0) | 64.0 ± 3.1 ** (90.4 ± 2.6) | 97.3 ± 0.3 ** (82.2 ± 4.2) | 19.1 |
Methyl angolensate (7) [17] | 0.0 ± 5.9 (100.0 ± 2.4) | 10.1 ± 4.2 (108.8 ± 11.0) | 20.0 ± 8.1 (108.8 ± 5.5) | 42.2 ± 3.5 ** (111.0 ± 4.5) | 24.0 ± 4.2 * (78.1 ± 5.3 #) | > 100 |
Epoxyazadiradione (8) | 0.0 ± 0.8 (100.0 ± 4.1) | 10.5 ± 0.9 * (99.6 ± 2.9) | 56.0 ± 4.0 ** (94.8 ± 2.3) | 102.6 ±4.0 ** (81.9 ± 2.7) | 112.3 ± 0.7 ** (10.0 ± 0.5 #) | 8.2 |
17β-Hydroxyazadiradione (9) | 0.0 ± 4.9 (100.0 ± 1.8) | −10.4 ± 6.8 (95.4 ± 5.2) | 9.4 ± 7.1 (94.4 ± 1.4) | 65.1 ± 4.5 ** (94.8 ± 4.9) | 97.4 ± 0.7 ** (84.8 ± 3.6) | 20.3 |
Carapanolide C (10) | 0.0 ± 2.6 (100.0 ± 3.4) | 4.2 ± 8.8 (96.0 ± 4.1) | 20.8 ± 5.0 ** (98.9 ± 3.4) | 20.2 ± 4.9 (91.8 ± 2.8) | 13.2 ± 1.9 (80.0 ± 4.4) | >100 |
Carapanolide R (11) | 0.0 ± 1.3 (100.0 ± 1.0) | 4.0 ± 2.2 (95.1 ± 1.8) | 8.9 ± 2.3 (98.0 ± 1.7) | 17.4 ± 1.3 (106.0 ± 1.9) | 75.6 ± 1.2 ** (118.4 ± 1.0) | 68.3 |
Carapanolide S (12) | 0.0 ± 2.8 (100.0 ± 0.7) | 2.5 ± 1.2 (97.9 ± 2.7) | 15.9 ± 1.3 ** (93.8 ± 2.0) | 72.2 ± 3.6 ** (96.8 ± 4.4) | 99.8 ± 0.4 ** (73.7 ± 3.8 #) | 15.5 |
Carapanolide M (13) | 0.0 ± 2.2 (100.0 ± 2.3) | −1.1 ± 2.7 (99.2 ± 0.6) | 3.2 ± 2.8 (95.1 ± 1.3) | 30.3 ± 3.1 ** (94.2 ± 2.9) | 85.1 ± 1.5 ** (111.9 ± 1.6) | 41.6 |
Carapanolide Q (14) | 0.0 ± 2.4 (100.0 ± 2.8) | 1.9 ± 0.7 (99.8 ± 1.6) | 14.4 ± 2.2 (96.3 ± 1.6) | 44.3 ± 1.1 ** (95.5 ± 4.1) | 75.3 ± 3.5 ** (115.5 ± 2.2) | 38.0 |
Carapanolide O (15) | 0.0 ± 2.5 (100.0 ± 4.6) | −2.5 ± 5.4 (104.1 ± 2.5) | 14.7 ± 8.2 (107.9 ± 2.7) | 6.9 ± 5.0 (106.7 ± 2.5) | 102.5 ± 3.2 ** (108.7 ± 5.2) | 46.0 |
Guianolide A (16) | 0.0 ± 1.8 (100.9 ± 0.9) | 1.9 ± 3.2 (96.9 ± 1.8) | 3.2 ± 1.4 (101.5 ± 1.9) | 12.7 ± 1.6 (98.7 ± 1.8) | 71.3 ± 3.2 ** (106.2 ± 1.6) | 77.9 |
Carapanolide A (17) | 0.0 ± 1.5 (100.0 ± 1.8) | −0.6 ± 2.1 (103.0 ± 2.6) | 1.2 ± 2.0 (103.9 ± 4.3) | 41.1 ± 1.0 ** (109.5 ± 4.3) | 4.9 ± 1.8 (91.3 ± 1.6) | > 100 |
l-NMMA [33,36] | 0.0 ± 3.1 (100.0 ± 0.9) | 1.4 ± 2.8 (101.1 ± 5.7) | 19.9 ± 2.8 ** (100.7 ± 6.2) | 43.0 ± 2.1 ** (102.6 ± 4.2) | 70.9 ± 1.6 ** (106.4 ± 4.6) | 36.0 |
CAPE [33,36] | 0.0 ± 2.1 (100.0 ± 1.5) | 5.9 ± 5.2 (95.4 ± 0.7) | 44.4 ± 3.2 ** (70.0 ± 4.0 #) | 86.2 ± 1.1 ** (71.4 ± 6.0 #) | 99.6 ± 0.1 ** (53.0 ± 1.4 #) | 11.0 |
Treatment | Inhibition (%) | ||||
---|---|---|---|---|---|
0 µM | 1 µM | 3 µM | 10 µM | 30 µM | |
Gedunin (1) | 0.0 ± 2.1 | 4.5 ± 1.9 | 21.8 ± 3.7 ** | 38.1 ± 3.8 ** | 36.5 ± 4.1 ** |
6α-Acetoxygedunin (2) | 0.0 ± 1.6 | 10.9 ± 1.0 ** | 23.2 ± 1.8 ** | 36.3 ± 2.1 ** | 37.3 ± 1.4 ** |
7-Deacetoxy-7-oxogedunin (3) | 0.0 ± 1.1 | 5.8 ± 1.5 | 26.7 ± 4.5 ** | 58.6 ± 7.2 ** | 68.7 ± 4.8 ** |
7-Deacetoxy-7α-hydroxygedunin (4) | 0.0 ± 0.3 | −6.5 ± 2.4 | 2.7 ± 2.3 | 36.5 ± 1.8 ** | |
Andirolide H (5) | 0.0 ± 0.8 | −6.6 ± 3.6 | −0.7 ± 1.2 | 7.6 ± 1.1 | 39.2 ± 1.7 ** |
6α-Hydroxygedunin (6) | 0.0 ± 1.3 | 8.1 ± 1.9 | 6.7 ± 1.5 | 12.1 ± 3.0 | 28.3 ± 1.7 ** |
Methyl angolensate (7) | 0.0 ± 1.4 | −0.5 ± 3.5 | 0.6 ± 2.9 | 13.3 ± 2.6 * | 24.6 ± 2.9 ** |
Epoxyazadiradione (8) | 0.0 ± 5.3 | 13.7 ± 3.9 | 39.1 ± 6.5 ** | 91.5 ± 11.4 ** | |
17β-Hydroxyazadiradione (9) | 0.0 ± 1.5 | 14.1 ± 3.4 | 23.9 ± 3.9 ** | 64.0 ± 3.3 ** | 91.3 ± 8.2 ** |
Carapanolide C (10) | 0.0 ± 3.7 | 4.9 ± 2.1 | 14.2 ± 3.2 | 27.7 ± 4.3 ** | 54.5 ± 5.5 ** |
Carapanolide R (11) | 0.0 ± 4.1 | −6.3 ± 4.7 | −1.3 ± 3.8 | 31.7 ± 3.8 ** | |
Carapanolide S (12) | 0.0 ± 1.5 | −5.5 ± 2.2 | −1.4 ± 1.5 | −2.5 ± 1.2 | |
Carapanolide M (13) | 0.0 ± 6.5 | −1.5 ± 7.1 | 7.0 ± 4.4 | −5.1 ± 6.2 | |
Carapanolide Q (14) | 0.0 ± 5.5 | 8.6 ± 4.4 | 1.3 ± 4.2 | 9.2 ± 2.5 | |
Carapanolide O (15) | 0.0 ± 6.5 | 6.3 ± 4.3 | 1.0 ± 6.4 | 1.5 ± 4.1 | |
Guianolide A (16) | 0.0 ± 2.9 | −6.2 ± 5.2 | −4.5 ± 1.9 | −7.3 ± 3.0 | |
Carapanolide A (17) | 0.0 ± 3.7 | 8.8 ± 6.5 | 21.5 ± 5.5 ** | 58.2 ± 4.7 ** | |
Treatment | Inhibition (%) | ||||
0 µM | 3 µM | 10 µM | 30 µM | 100 µM | |
Silybin [36] | 0.0 ± 2.6 | 5.3 ± 2.8 | 22.0 ± 3.8 ** | 48.0 ± 4.1 ** | 50.8 ± 3.9 ** |
© 2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Ninomiya, K.; Miyazawa, S.; Ozeki, K.; Matsuo, N.; Muraoka, O.; Kikuchi, T.; Yamada, T.; Tanaka, R.; Morikawa, T. Hepatoprotective Limonoids from Andiroba (Carapa guianensis). Int. J. Mol. Sci. 2016, 17, 591. https://doi.org/10.3390/ijms17040591
Ninomiya K, Miyazawa S, Ozeki K, Matsuo N, Muraoka O, Kikuchi T, Yamada T, Tanaka R, Morikawa T. Hepatoprotective Limonoids from Andiroba (Carapa guianensis). International Journal of Molecular Sciences. 2016; 17(4):591. https://doi.org/10.3390/ijms17040591
Chicago/Turabian StyleNinomiya, Kiyofumi, Seiya Miyazawa, Kaiten Ozeki, Natsuko Matsuo, Osamu Muraoka, Takashi Kikuchi, Takeshi Yamada, Reiko Tanaka, and Toshio Morikawa. 2016. "Hepatoprotective Limonoids from Andiroba (Carapa guianensis)" International Journal of Molecular Sciences 17, no. 4: 591. https://doi.org/10.3390/ijms17040591