Dehydroepiandrosterone inhibits complex I of the mitochondrial respiratory chain and is neurotoxic in vitro and in vivo at high concentrations

Toxicological Sciences

Volumn 93, Issue 2, 2006, Pages 348-356

  Safiulina, Dzhamilja ^a   Peet, Nadezhda ^a   Seppet, Enn ^a   Zharkovsky, Alexander ^a   Kaasik, Allen ^a  

^a UNIVERSITY OF TARTU   (Estonia)

Author keywords

Complex I of the mitochondrial electron transport chain; Dehydroepiandrosterone; Mitochondria; Neurodegeneration; Neurosteroids; Neurotoxicity

Indexed keywords

DIHYDROXYPHENYLACETIC ACID; DOPAMINE; GLUCOSE; PRASTERONE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE DEHYDROGENASE (UBIQUINONE);

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BRAIN CORTEX; BRAIN NERVE CELL; CELL CULTURE; CELL DEATH; CELL LOSS; CELL MEMBRANE PERMEABILITY; CONCENTRATION RESPONSE; CONTROLLED STUDY; ELECTRON TRANSPORT; ENERGY EXPENDITURE; HIPPOCAMPUS; HYPOGLYCEMIA; IN VITRO STUDY; IN VIVO STUDY; MALE; MITOCHONDRIAL RESPIRATION; MOTOR DYSFUNCTION; MOUSE; NEUROTOXICITY; NONHUMAN; RAT; RESPIRATORY CHAIN;

ANIMALS; APOPTOSIS; CELLS, CULTURED; DEHYDROEPIANDROSTERONE; DOSE-RESPONSE RELATIONSHIP, DRUG; ELECTRON TRANSPORT; ELECTRON TRANSPORT COMPLEX I; ENERGY METABOLISM; MALE; MICE; MICE, INBRED BALB C; MITOCHONDRIA; MOTOR ACTIVITY; NEURONS; RATS; RATS, WISTAR;

ANIMALIA;

EID: 33748752316     PISSN: 10966080     EISSN: 10960929     Source Type: Journal    
DOI: 10.1093/toxsci/kfl064     Document Type: Article

References (59)

1. Aragno, M., Parola, S., Brignardello, E., Mauro, A., Tamagno, E., Manti, R., Danni, O., and Boccuzzi, G. (2000). Dehydroepiandrosterone prevents oxidative injury induced by transient ischemia/reperfusion in the brain of diabetic rats. Diabetes 49, 1924-1931.
2. Baulieu, E. E., and Robel, P. (1998). Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) as neuroactive neurosteroids. Proc. Natl. Acad. Sci. U.S.A. 95, 4089-4091.
3. Baulieu, E. E., Thomas, G., Legrain, S., Lahlou, N., Roger, M., Debuire, B., Faucounau, V., Girard, L., Hervy, M. P., Latour, F., et al. (2000). Dehydroepiandrosterone (DHEA), DHEA sulfate, and aging: Contribution of the DHEAge Study to a sociobiomedical issue. Proc. Natl. Acad. Sci. U.S.A. 97, 4279-4284.
4. Bergeron, R., de Montigny, C., and Debonnel, G. (1996). Potentiation of neuronal NMDA response induced by dehydroepiandrosterone and its suppression by progesterone: Effects mediated via sigma receptors. J. Neurosci. 16, 1193-1202.
5. Betarbet, R., Sherer, T. B., MacKenzie, G., Garcia-Osuna, M., Panov, A. V., and Greenamyre, J. T. (2000). Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat. Neurosci. 3, 1301-1306.
6. Brunmair, B., Gras, F., Neschen, S., Roden, M., Wagner, L., Waldhäusl, W., and Fürnsinn, C. (2001). Direct thiazolidinedione action on isolated rat skeletal muscle fuel handling is independent of peroxisome proliferator-activated receptor-mediated changes in gene expression. Diabetes 50, 2309-2315.
7. Brunmair, B., Staniek, K., Gras, F., Scharf, N., Althaym, A., Clara, R., Roden, M., Gnaiger, E., Nohl, H., Waldhausl, W., et al. (2004). Thiazolidinediones, like metformin, inhibit respiratory complex I: A common mechanism contributing to their antidiabetic actions? Diabetes 53, 1052-1059.
8. Calabrese, V. P., Isaacs, E. R., and Regelson, W. (1990). Dehydroepiandrosterone in multiple sclerosis: Positive effects on the fatigue syndrome in a non-randomized study. In The Biological Role of Dehydroepiandrosterone (DHEA) (M. Kalimi and W. Regelson, Eds.), pp. 95-100. Walter de Gruyter, New York.
9. Caparros-Lefebvre, D., Sergeant, N., Lees, A., Camuzat, A., Daniel, S., Lannuzel, A., Brice, A., Tolosa, E., Delacourte, A., and Duyckaerts, C. (2002). Guadeloupean parkinsonism: A cluster of progressive supranuclear palsy-like tauopathy. Brain 125, 801-811.
10. Champy, P., Hoglinger, G. U., Feger, J., Gleye, C., Hocquemiller, R., Laurens, A., Guerineau, V., Laprevote, O., Medja, F., Lombes, A., et al. (2004). Annonacin, a lipophilic inhibitor of mitochondrial complex I, induces nigral and striatal neurodegeneration in rats: Possible relevance for atypical Parkinsonism in Guadeloupe. J. Neurochem. 88, 63-69.
11. Chen, Q., Hoppel, C. L., and Lesnefsky, E. J. (2006). Blockade of electron transport before cardiac ischemia with the reversible inhibitor amobarbital protects rat heart mitochondria. J. Pharmacol. Exp. Ther. 316, 200-207.
12. Chili, H. W., Chiu, H. F., Tang, K. S., Chang, F. R., and Wu, Y. C. (2001). Bullatacin, a potent antitumor annonaceous acetogenin, inhibits proliferation of human hepatocarcinoma cell line 2.2.15 by apoptosis induction. Life Sci. 69, 1321-1331.
13. Chiu, H. F., Chih, T. T., Hsian, Y. M., Tseng, C. H., Wu, M. J., and Wu, Y. C. (2003). Bullatacin, a potent antitumor Annonaceous acetogenin, induces apoptosis through a reduction of intracellular cAMP and cGMP levels in human hepatoma 2.2.15 cells. Biochem. Pharmacol. 65, 319-327.
14. Coates, G., Nissim, I., Battarbee, H., and Welbourne, T. (2002). Glitazones regulate glutamine metabolism by inducing a cellular acidosis in MDCK cells. Am. J. Physiol. 283, E729-E737.
15. Cunningham, M. L., Soliman, M. S., Badr, M. Z., and Matthews, H. B. (1995). Rotenone, an anticarcinogen, inhibits cellular proliferation but not peroxisome proliferation in mouse liver. Cancer Lett. 95, 93-97.
16. Davis, T. M., Jackson, D., Davis, W. A., Bruce, D. G., and Chubb, P. (2001). The relationship between metformin therapy and the fasting plasma lactate in type 2 diabetes: The Fremantle Diabetes Study. Br. J. Clin. Pharmacol. 52, 137-144.
17. Debonnel, G., Bergeron, R., and de Montigny, C. (1996). Potentiation by dehydroepiandrosterone of the neuronal response to N-methyl-aspartate in the CA3 region of the rat dorsal hippocampus: An effect mediated via sigma receptors. J. Endocrinol. 150, S33-S42.
18. Dello Russo, C., Gavrilyuk, V., Weinberg, G., Almeida, A., Bolanos, J. P., Palmer, J., Pelligrino, D., Galea, E., and Feinstein, D. L. (2003). Peroxisome proliferator-activated receptor thiazolidinedione agonists increase glucose metabolism in astrocytes. J. Biol. Chem. 278, 5828-5836.
19. Di Monaco, M., Pizzini, A., Gatto, V., Leonardi, L., Gallo, M., Brignardello, E., and Boccuzzi, G. (1997). Role of glucose-6-phosphate dehydrogenase inhibition in the antiproliferative effects of dehydroepiandrosterone on human breast cancer cells. Br. J. Cancer. 75, 589-592.
20. Evans, J. M., Donnelly, L. A., Emslie-Smith, A. M., Alessi, D. R., and Morris, A. D. (2005). Metformin and reduced risk of cancer in diabetic patients. BMJ 330, 1304-1305.
21. 2 production from glucose and palmitate in isolated rat skeletal muscle. J. Pharmacol. Exp. Ther. 293, 487-493.
22. Gayosso, V., Montano, L. F., and Lopez-Marure, R. (2006). DHEA-induced antiproliferative effect in MCF-7 cells is androgen- and estrogen receptor-independent. Cancer J. 12, 160-165.
23. Gorell, J. M., Johnson, C. C., Rybicki, B. A., Peterson, E. L., and Richardson, R. J. (1998). The risk of Parkinson's disease with exposure to pesticides, farming, well water, and rural living. Neurology 50, 1346-1350.
24. Hansen, W. H., Davis, K. J., and Fitzhugh, O. G. (1965). Chronic toxicity of cube. Toxicol. Appl. Pharmacol. 7, 535-542.
25. Ichikawa, H., Takagi, T., Uchiyama, K., Higashihara, H., Katada, K., Isozaki, Y., Naito, Y., Yoshida, N., and Yoshikawa T. (2004). Rotenone, a mitochondrial electron transport inhibitor, ameliorates ischemia-reperfusion-induced intestinal mucosal damage in rats. Redox Rep. 9, 313-316.
26. Kaasik, A., Kalda, A., Jaako, K., and Zharkovsky, A. (2001). Dehydroepiandrosterone sulphate prevents oxygen-glucose deprivation-induced injury in cerebellar granule cell culture. Neuroscience 102, 427-432.
27. Kaasik, A., Safiulina, D., Kalda, A., and Zharkovsky, A. (2003). Dehydroepiandrosterone with other neurosteroids preserve neuronal mitochondria from calcium overload. J. Steroid Biochem. Mol. Biol. 87, 97-103.
28. Kawai, S., Yahata, N., Nishida, S., Nagai, K., and Mizushima, Y. (1995). Dehydroepiandrosterone inhibits B16 mouse melanoma cell growth by induction of differentiation. Anticancer Res. 15, 427-431.
29. Kimonides, V. G., Khatibi, N. H, Svendsen, C. N., and Herbert, J. (1998). Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS) protect hippocampul neurons against excitatory amino acid-induced neurotoxicity. Proc. Nalt. Acad. Sci. U.S.A. 95, 1852-1857.
30. Kopplow, K., Wayss, K., Enzmann, H., and Mayer, D. (2005). Dehydroepiandrosterone causes hyperplasia and impairs regeneration in rat liver. Int. J. Oncol. 27, 1551-1558.
31. Kunst, A., Draeger, B., and Ziegenhorn, J. (1988). D-Glucose. In Methods of Enzymatic Analysis (H. U. Bergmeyer, Ed.), 3rd ed., Vol. VI, pp. 163-172. VCH Publishers (UK) Ltd, Cambridge, UK.
32. Lannuzel, A., Michel, P. P., Hoglinger, G. U., Champy, P., Jousset, A., Medja, F., Lombes, A., Darios, F., Gleye, C., Laurens, A., et al. (2003). The mitochondrial complex I inhibitor annonacin is toxic to mesencephalic dopaminergic neurons by impairment of energy metabolism. Neuroscience 121, 287-296.
33. Lapchak, P. A., Chapman, D. F., Nunez, S. Y., and Zivin, J. A. (2000). Dehydroepiandrosterone sulfate is neuroprotective in a reversible spinal cord ischemia model: Possible involvement of GABA(A) receptors. Stroke 31, 1953-1956.
34. Lesnefsky, E. J., Chen, Q., Moghaddas, S., Hassan, M. O., Tandler, B., and Hoppel, C. L. (2004). Blockade of electron transport during ischemia protects cardiac mitochondria. J. Biol. Chem. 279, 47961-47967.
35. Li, H., Klein, G., Sun, P., and Buchan, A. M. (2001). Dehydroepiandrosterone (DHEA) reduces neuronal injury in a rat model of global cerebral ischemia. Brain Res. 888, 263-266.
36. Luft, F. C. (2001). Lactic acidosis update for critical care clinicians. J. Am. Soc. Nephrol. 12, S15-S19.
37. Mayer, D., and Forstner, K. (2004). Impact of dehydroepiandrosterone on hepatocarcinogenesis in the rat. Int. J. Oncol. 25, 1021-1030.
38. Mayer, D., Forstner, K., and Kopplow, K. (2003). Induction and modulation of hepatic preneoplasia and neoplasia in the rat by dehydroepiandrosterone. Toxicol. Pathol. 31, 1-10.
39. McIntosh, M. K., Pan, J. S., and Berdanier, C. D. (1993). In vitro studies on the effects of dehydroepiandrosterone and corticosterone on hepatic steroid receptor binding and mitochondrial respiration. Comp. Biochem. Physiol. Comp. Physiol. 104, 147-153.
40. Metzger, C., Mayer, D., Hoffmann, H., Bocker, T., Hobe, G., Benner, A., and Bannasch, P. (1995). Sequential appearance and ultrastructure of amphophilic cell foci, adenomas, and carcinomas in the liver of male and female rats treated with dehydroepiandrosterone. Toxicol. Pathol. 23, 591-605.
41. Mohan, P. F., and Cleary, M. P. (1989). Dehydroepiandrosterone and related steroids inhibit mitochondrial respiration in vitro. Int. J. Biochem. 21, 1103-1107.
42. Mortola, J. F., and Yen, S. S. (1990). The effects of oral dehydroepiandrosterone on endocrine-metabolic parameters in postmenopausal women. J. Clin. Endocrinol. Metab. 71, 696-704.
43. Musi, N., Hirshman, M. F., Nygren, J., Svanfeldt, M., Bavenholm, P., Rooyackers, O., Zhou, G., Williamson, J. M., Ljunqvist, O., Efendic, S., et al. (2002). Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes 51, 2074-2081.
44. Nicklas, W. J., Vyas, I., and Heikkila, R. E. (1985). Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenyl-pyridine, a metabolite of the neurotoxin, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. Life Sci. 36, 2503-2508.
45. Noll, F. (1988). L-(+)-Lactate. In Methods of Enzymatic Analysis (H. U. Bergmeyer, Ed.), 3rd ed., Vol. VI, pp. 582-588. VCH Publishers (UK) Ltd, Cambridge, UK.
46. Owen, M. R., Doran, E., and Halestrap, A. P. (2000). Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem. J. 348, 607-614.
47. Pauwels, P. J., Opperdoes, F. R., and Trouet, A. (1985). Effects of antimycin, glucose deprivation, and serum on cultures of neurons, astrocytes, and neuroblastoma cells. J. Neurochem. 44, 143-148.
48. Preininger, K., Stingl, H., Englisch, R., Fürnsinn, C., Graf, J., Waldhäusl, W., and Roden, M. (1999). Acute troglitazone action in isolated perfused rat liver. Br. J. Pharmacol. 126, 372-378.
49. Ramsay, R. R., Youngster, S. K., Nicklas, W. J., McKeown, K. A., Jin, Y. Z., Heikkila, R. E., and Singer, T. P. (1989). Structural dependence of the inhibition of mitochondrial respiration and of NADH oxidase by l-methyl-4-phenylpyridinium (MPP+) analogs and their energized accumulation by mitochondria. Proc. Natl. Acad Sci. U.S.A. 86, 9168-9172.
50. Sherer, T. B., Kim, J. H., Betarbet, R., and Greenamyre, J. T. (2003). Subcutaneous rotenone exposure causes highly selective dopaminergic degeneration and alpha-synuclein aggregation. Exp. Neurol. 179, 9-16.
51. Silvagno, F., Guarnieri, V., Capizzi, A., and Pescarmona, G. P. (2002). Synergistic effect of retinoic acid and dehydroepiandrosterone on differentiation of human neuroblastoma cells. FEBS Lett. 532, 153-158.
52. Sonka, J., Hilgertova, J., Sevcik, J., and Kratochvil, O. (1978). In vitro and in vivo inhibitory effect of dehydroepiandrosterone on respiration. Endocrinol. Exp. 12, 165-169.
53. Sousa, A., and Ticku, M. K. (1997). Interactions of the neurosteroid dehydroepiandrosterone sulfate with the GABA(A) receptor complex reveals that it may act via the picrotoxin site. J. Pharmacol. Exp. Ther. 282, 827-833.
54. Tormo, J. R., Gallardo, T., Peris, E., Bermejo, A., Cabedo, N., Estornell, E., Zafra-Polo, M. C., and Cortes, D. (2003). Inhibitory effects on mitochondrial complex I of semisynthetic mono-tetrahydrofuran acetogenin derivatives. Bioorg. Med. Chem. Lett. 13, 4101-4105.
55. Vaarmann, A., and Kask, A. (2001). Cocaine and amphetamine-regulated transcript peptide (CART(62-76))-induced changes in regional monoamine levels in rat brain. Neuropeptides 35, 292-296.
56. Weber, E., Moore, M. A., and Bannasch, P. (1988). Phenotypic modulation of hepatocarcinogenesis and reduction in N-nitrosomorpholine induced hemangiosarcoma and adrenal lesion development in Sprague-Dawley rats by dehydroepiandrosterone. Carcinogenesis 9, 1191-1195.
57. West, M. J., Slomianka, L., and Gundersen, H. J. (1991). Unbiased stereological estimation of the total number of neurons in the subdivisions of the rat hippocampus using the optical fractionator. Anat. Rec. 231, 482-497.
58. Yang, N. C., Jeng, K. C., Ho, W. M., and Hu, M. L. (2002). ATP depletion is an important factor in DHEA-induced growth inhibition and apoptosis in BV-2 cells. Life Sci. 70, 1979-1988.
59. Zhu, X. F., Liu, Z. C., Xie, B. F., Li, Z. M., Feng, G. K., Xie, H. H., Wu, S. J., Yang, R. Z., Wei, X. Y., and Zeng, Y. X. (2002). Involvement of caspase-3 activation in squamocin-induced apoptosis in leukemia cell line HL-60. Life Sci. 70, 1259-1269.