Abstract
Selenium, long recognised as an important ‘dietary antioxidant’, is now known to be an essential component of the active sites of a number of enzymes, including the glutathione peroxidase selenoenzyme family which scavenge hydroperoxides to prevent cellular damage. Dietary selenium deficiency has been linked to diseases as diverse as cancer, heart disease, arthritis and AIDS, and epidemiological evidence is now emerging for the beneficial effects of selenium supplementation. Thus, the pharmacology, biology and biochemistry of selenium metabolism have become subjects of considerable interest, which are spurring efforts to develop synthetic selenium-containing compounds as potential therapeutic agents.
Phenylaminoalkyl selenides were developed in the authors’ laboratories as novel, selenium-based pharmacological agents. We demonstrated that these compounds exhibited dose-dependent antihypertensive activity in spontaneously hypertensive rats. Biochemical studies established that as a consequence of the redox properties of their selenium moieties, these phenylaminoalkyl selenides possessed the remarkable property of propagating a cycle of turnover-dependent local depletion of reduced ascorbate when processed by the key enzyme of catecholamine metabolism, dopamine-β-monooxygenäse.
On the basis of inductively coupled plasma/mass spectroscopic analyses, corroborated by operant behaviour and locomotor activity investigations, an orally-active phenylaminoalkyl selenide with restricted CNS permeability was successfully developed. To our knowledge, this compound -4-hydroxy-α-methyl-phenyl-2-aminoethyl selenide —is the first orally active, selenium-based anti-hypertensive compound ever reported. In the future, we anticipate more widespread efforts to incorporate selenium into rationally designed pharmaceutical agents, with the goal of developing novel compounds which may be of therapeutic benefit toward a variety of human diseases.
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References
Walter R, Schwartz IL, Roy J. Can selenoamino acids act as reversible biological antioxidants? Ann N Y Acad Sci 1972; 192: 175–80
Leibovitz B, Hu M, Tappel AL. Dietary supplements of vitamin E, b-carotene, coenzyme Q10, and selenium protect tissues against lipid peroxidation in rat tissue slices. J Nutr 1990; 120: 97–104
Caldwell KA, Tappel AL. Reactions of seleno-and sulfoamino acids with hydroperoxides. Biochemistry 1964; 3: 1643–7
Olcott HS, Brown WD, Van der Veen J. Selenomethionine as an antioxidant. Nature 1961; 191: 1201–2
Hamilton JW, Tappel AL. Lipid antioxidant activity in tissues and proteins of selenium-fed animals. J Nutr 1963; 79: 493–502
Fox JM. Selenium: nutritional implications and prospects for therapeutic medicine. Methods Find Exp Clin Pharmacol 1992; 14: 275–87
Parnham MJ, Graf E. Seleno-organic compounds and the therapy of hydroperoxide-linked pathological conditions. Biochem Pharmacol 1987; 36: 3095–102
Baum MK, Shor-Posner G, Lai S, et al. High risk of HIV-related mortality is associated with selenium deficiency. J Acquir Immune Defic Syndr Hum Retrovirol 1997; 15: 370–4
Clark LC, Combs GF Jr, Turnbull BW, et al. Effect of selenium supplementation for cancer prevention in patients with carcinoma of the skin. JAMA 1996; 276: 1957–63
Subcommittee on the Tenth Edition of the RDA’s Food and Nutrition Board, Commission on Life Sciences, National Research Council Recommended Dietary Allowances. 10th ed. Washington DC: National Academy Press, 1989
Stadtman TC. Selenocysteine. Annu Rev Biochem 1996; 65: 83–100
Ursini F, Bindoli A. The role of selenium peroxidases in the protection against oxidative damage of membranes. Chem Phys Lipids 1987; 44: 255–76
Voet D, Voet JG. Biochemistry. 2nd ed. New York: Wiley, 1995
Beck MA, Shi Q, Morris VC, et al. Rapid genomic evolution of a non-virulent Coxsackievirus B3 in selenium-deficient mice results in selection of identical virulent isolates. Nature Med 1995; 1: 433–6
Parnham MJ, Graf E. Pharmacology of synthetic organic selenium compounds. Prog Drug Res 1991; 36: 9–47
Shamberger RJ. Synthetic forms of selenium and their chemotherapeutic uses. In: Shamberger RJ, editor. Biochemistry of selenium. New York: Plenum, 1983: 273–310
Klayman DL. Selenium compounds as potential therapeutic agents. In: Klayman DL, Gunther WH, editors. Organic selenium compounds: their chemistry and biology. New York: Wiley, 1973: 727–61
Parnham MJ. The pharmaceutical potential of selenium. Pharm News 1996; 3: 7–10
Hoshida S, Aoki K, Nishida M, et al. Effects of preconditioning with ebselen on glutathione metabolism and stress protein expression. J Pharmacol Exp Ther 1987; 218: 1471–5
Herman HH, Husain PA, Colbert JE, et al. The enantiomeric specificity of the antihypertensive activity of l-(phenylthio)-2-aminopropane, a synthetic substrate analogue for dopamine β-monooxygenase. J Med Chem 1991; 34: 1082–5
Kruse LI, Kaiser C, DeWolf WE Jr, et al. Substituted 1-benzyl-imidazole-2-thiols as potent and orally active inhibitors of dopamine b-hydroxylase. J Med Chem 1986; 29: 887–9
May SW, Herman HH, Roberts SF, et al. Ascorbate depletion as a consequence of product recycling during dopamine β-monooxygenase catalyzed selenoxidation. Biochem 1987; 26: 1626–32
May SW, Wimalasena K, Herman HH, et al. Novel antihypertensives targeted at dopamine β-monooxygenase: turnover-dependent cofactor depletion by phenyl aminoethyl selenide. J Med Chem 1988; 31: 1066–8
Wimalasena K, Herman HH, May SW. Effects of dopamine β-monooxygenase substrate analogs on ascorbate levels and norepinephrine synthesis in adrenal chromaffin granule ghosts. J Biol Chem 1989; 264: 124–30
Herman HH, Wimalasena K, Fowler LC, et al. Demonstration of the ascorbate dependence of membrane-bound dopamine β-monooxygenase in adrenal chromaffin granule ghosts. J Biol Chem 1988; 263: 666–72
May SW, Young FK, Powers JL, et al. Mechanism-based inactivation of dopamine beta-monooxygenase in adrenal chromaffin cells. Biochem Biophys Res Commun 1996; 228: 278–84
Pollock SH, Herman HH, Fowler LC, et al. Demonstration of the antihypertensive activity of phenyl-2-aminoethyl selenide. J Pharm Exp Ther 1988; 246: 227–34
Rimmer SJ, Church MK. The pharmacology and mechanism of actions of histamine H1-antagonists. Clin Exp Allergy 1990: 20 Suppl. 2: 3–17
Brown JH. In: Gilman AG, Rall TW, Nies AS, et al. Goodman and Gilman’s pharmacological basis of therapeutics. 8th ed. New York: McGraw-Hill, Inc, 1990: 159
Nadelmann J, Frishman WH. Clinical use of beta-adrenoceptor blockade in systemic hypertension. Drugs 1990; 39: 862–76
May SW, Wang L, Gill MM, et al. An orally active selenium-based antihypertensive agent with restricted CNS permeability. J Pharm Exp Ther 1997; 283: 470–7
Selenium. In: Trace elements in human nutrition and health. Geneva: World Health Organization, 1996: 105–22
Hu YJ, Chen Y, Zhang YQ, et al. The protective role of selenium on the toxicity of cisplatin-contained chemotherapy regimen in cancer patients. Biol Trace Elem Res 1997; 56: 331–41
Ihnat M, editor. Occurrence and distribution of selenium. Boca Raton (FL): CRC Press Inc., 1989
Zingaro RA, Cooper WC, editors. Selenium. New York: Van Nostrand Reinhold, 1974
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May, S.W., Pollock, S.H. Selenium-Based Antihypertensives. Drugs 56, 959–964 (1998). https://doi.org/10.2165/00003495-199856060-00001
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DOI: https://doi.org/10.2165/00003495-199856060-00001