CA2326771A1 - Agents and methods for modulation of zinc transfer by metallothionein - Google Patents

Agents and methods for modulation of zinc transfer by metallothionein Download PDF

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CA2326771A1
CA2326771A1 CA002326771A CA2326771A CA2326771A1 CA 2326771 A1 CA2326771 A1 CA 2326771A1 CA 002326771 A CA002326771 A CA 002326771A CA 2326771 A CA2326771 A CA 2326771A CA 2326771 A1 CA2326771 A1 CA 2326771A1
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chelates
glutathione
zinc
metallothionein
disulfide
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Bert L. Vallee
Wolfgang Maret
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Endowment for Research in Human Biology Inc
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    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
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    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
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    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
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    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
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Abstract

A method is provided for the treatment of diseases of plants and animals whe re such diseases involve disturbance of zinc homeostasis. The method involves administration of therapeutic agents that after cellular oxidation potential so as to oxidize metallothionein and thereby release zinc ions, or as to maintain metallothionein in a reduced state so as to prevent transfer of zin c from metallothionein to zinc acceptors.

Description

AGENTS AND METHODS FOR MODULATION OF ZINC TRANSFER BY
METALLOTHIONEIN -This application claims priority to U.S. provisional applications Serial Number 60/079,969, filed March 30, 1998, and Serial Number 60/084,953, filed May 11, 1998.
1. INTRODUCTION
The present invention relates to control of zinc metabolism mediated by metallothioneins. Metallothioneins are both the predominant cellular reservoir for bioavailable zinc and the primary shuttle for zinc transfer among biomolecules. Agents are provided that enhance or prevent the release of zinc from metallothioneins and thereby affect metabolic pathways that depend on the availability or uptake of zinc.
2. BACKGROUND OF THE INVENTION
2.1. METALLOTHIONEIN
Metallothionein (MT) was discovered in 1957 (Margoshes, M. and Vallee, B.
L., 1957, J. Am. Chem. Soc. 79. 4813). By all counts it is a most unusual and unconventional protein (Vallee, B.L., 1979, Experientia Suppl. 34, 19-40;
Vallee, B.L., 1987, Experientia Suppl. 52, 5-16; Vallee, B. L., 1991, Meth. Enzymol. 205, 3-7; Vallee, B.L. and Maret, W., 1993, in Metallothionein III, eds. Suzuki, K. T., Imura, N. & Kimura, M. (Birkhauser, Basel), 1; Vallee, 1995. Neurochem. Interntl. 27, 23). One third of its 60+
amino acids are cysteines and eight are lysines. It contains neither aromatic amino acids nor histidine. MT usually binds seven zinc atoms, but it can also contain copper, cadmium, iron and traces of other metals. In an evolutionary sense it is a very old protein.
The composition of its two major isoproteins has changed only imperceptibly over time. The number of genes that code for human MTs could be as high as 17. MT-1 and MT-2 are the two prevalent forms, which are expressed, but whose physiological functions are unknown.
MT-3 was discovered only recently in brains from patients afflicted with Alzheimer's disease (Uchida, Y., Takio, K., Titani, K., Ihara, Y., and Tomonaga, M. ( I
991 ) Neuron 7, 337). Its discovery was based on the fact that it inhibits the growth of neurons. Thus far, it is the only MT that is known to exhibit such a specific biological function.
This isoform contains zinc and copper(I), but not cadmium or other metals. Multiple factors among them members of the nuclear hormone receptor family, interferons, inducers of the acute phase response, and metalloregulatory proteins, affect tissue- and isoprotein-specific gene expression. In addition there are numerous other agents that induce it but whose signalling pathways remain obscure. Thionein, the apoform of MT has never been isolated as such from any biological material. Apparently, upon its formation, it instantaneously combines with zinc, whose "free" concentration in the cell has been reported to be exceedingly low, i.e. in the nanomolar to picomolar range. All these facts suggest that MT must be biologically essential. This, indeed, has now been proven to be correct. MT-1/-2 knock-out mice become obese, demonstrating the involvement of MT in energy metabolism (Beattie, J.
H, Wood, A. M., Newman, A. M., Bremner, L, Choo, K. H. A., Michalska, A. E., Duncan, J. S., and Trayhurn, P., 1998, Proc. Natl. Acad. Sci. USA 95, 358).
While MT was discovered 40 years ago, the 3D structure of MT by both X-ray crystallography (Robbins, A. H. and Stout, C. D., 1991, Meth. Enzymol. 205, 485) and NMR spectroscopy (Wiithrich, K., 1991, Meth. Enzymol. 205, 502) has been reported only seven years ago. The structure has proved critical to efforts designed to establish its function. The protein has the shape of a dumb-bell and envelops the metals which it 1 S contains in two separate domains in a manner which effectively shields them from the environment. It is most remarkable that the metals are arranged in a cluster structure unique to biology. In one cluster four atoms are bound to eleven cysteines, five of which bridge the metals, and the other has three metal atoms and nine cysteines with three bridges.
The biological importance of zinc does not require elaboration at this point, since catalytic functions of zinc in enzymes and its structural functions in zinc finger proteins have been documented amply (Vallee, B. L. and Falchuk, K. F., 1993, Physiol.
Rev. 73, 79-118; Vallee, B. L. and Auld, D. S., 1993, Acc. Chem. Res. 26, 543). Zinc in MT is bound extremely tightly (KD about 10-'3 M) (Kagi, J. H. R., 1993, in Metallothionein lll, eds. Suzuki, K. T., Imura, N. & Kimura, M. (Birkhauser, Basel), pp. 29).
There have not been any indications how it is removed or added.
Findings that cast light on the circumstances under which zinc is released from MT have been reported. For example, the oxidative metal release from MT
by glutathione disulfide has been reported (Maret, W., 1994, Proc. Natl. Acad.
Sci. USA 91, 237), and exchange between MT and the zinc cluster in the Gal4 transcription factor has been demonstrated (Maret, W., Larsen, K. S., and Vallee, B. L., 1997, Proc.
Natl. Acad. Sci.
USA 94, 2233). These previous reports, however, do not report or suggest the methods and compositions of the present invention, and in fact, failed to appreciate the synergistic release of zinc by oxidants in the presence of glutathione; and failed to provide for zinc transfer on a physiologically significant time scale.

Zinc, in contrast to copper or iron, is redox-inert. Hence, the properties of zinc complexes are not altered by valence changes of the central atom: in a manner akin to those in iron or copper complexes. However, the redox state of the sulfur ligands can be changed.
2.2. DISORDERS OF THE CENTRAL NERVOUS SYSTEM
2.2.1. ALZHEIMER'S DISEASE
The cerebral cortexes of Alzheimer's disease ("AD") patients contain neurofibrillary tangles and senile (amyloid) plagues (D. M. A. Mann et al., 1988, Neuropathol. Appl. Neurol., 14, 177). These structures are associated with the dementia and memory loss that are characteristic of the disease.
2.2.2. PARKINSON'S DISEASE
Parkinson's disease involves degeneration of pigmented neuronal systems in the brain stem that leads to neuromediator dysfunction. The principal cytoskeletal pathology associated with Parkinson's disease is the Lewy body which predominately occurs in aminergic and other subcortical, spinal cord, and sympathetic ganglia neurons, and also to a lesser extent in the cerebral cortex. Lewy bodies in Parkinson's disease lead to a degeneration of the dopaminergic pathway of the pigmented neuronal systems as well as to a degeneration of other neuronal systems, and this degeneration leads to a complex set of functional deficits (M. Ebadi et al., 1996, Progr. Neurobiol., 48, l, and references therein).
2.2.3. EPILEPSY
Epilepsy, as a term, is broadly used to describe a group of disorders that are characterized by transient, recurrent, spontaneous paroxysms of a hyperactive brain resulting in seizures. The interictal (between seizures) state of the epileptogenic cortex displays brief, high-amplitude electrical impulses. Seizures are characterized by loss of inhibitory signals so as to foster hyperexcitability and hyperactivity.

2.3. APOPTOSIS AND INJURY FROM RADIATION OR CHEMOTHERAPY
Apoptosis is a physiological process whereby cells die without swelling, necrosis, or inflammation (J. F. R. Kerr et al., 1972, Brit. J. Cancer, 26, 239). Apoptosis, in a non-pathological context, is considered responsible for the selective deletion of cells during embryogenesis and for homeostasis in continuously renewing tissues (S.
Sen, 1992, Biol. Rev., 67, 287). In a pathological context, apoptosis is exhibited by cells in response to irradiation, oxidative stress, and to various chemical stimuli such as glucocorticoids (M. J.
Arends, A. H. Wyllie. 1991, Int. Rev. Exper. Pathol., 32, 223). Apoptosis has also been implicated as a process leading to aging (Z. Zakeri and R. A. Lockshin, 1994, Ann. Rev. NY
Acad. Sci., 719, 212) and cancer (J. F. R. Kerr et al., 1994, Cancer, 73, 2013). Biophysical and morphological indicators of apoptosis include fragmentation of endonuclear and chromatin DNA (Arends et al., 1990, Amer. J. Pathol., 136, 593) and compaction of cytoplasmic organelles into so-called "apoptotic bodies" (A. H. Wyllie et al., 1980, Int. Rev.
Cytol., 68, 251 ).
2.4. CARCINOGENESIS
A neoplasm, or tumor, is a cellular mass resulting from abnormal uncontrolled cell growth, which may cause swelling on the body surface, and which can be benign or malignant. Benign tumors generally remain localized. Malignant tumors are collectively termed cancers. The term "malignant" generally means that the tumor can invade and destroy neighboring body structures and spread to distant sites to cause death (for review, see Robbins and Angell, 1976, Basic Pathology, 2d Ed., W.B.
Saunders Co., Philadelphia, 68).
Effective treatment and prevention of cancer remains a long-felt need, and a major goal of biomedical research.
2.5. AUTOIMMUNE DISEASES
Autoimmune diseases are estimated to affect from 1 to 2 percent of the human population. Such diseases fall into two broad categories: organ-specific, and systemic diseases. Organ-specific autoimmune diseases include myasthenia gravis, Grave's disease, juvenile insulin-dependent diabetes, Addison's disease, and a host of others.
Systemic autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, scleroderma, rheumatic fever, as well as others. Such diseases result from a breakdown of immune tolerance to self antigens. Such breakdown may be due to any of one or several mechanisms: lack of elimination of self reactive clones, activation of anergic self reactive cells, or the release of sequestered self antigens that previously were inaccessible to the immune system.
2.5.1. SYSTEMIC LUPUS ERYTHEMATOSUS
Systemic lupus erythematosus is characterized by inflammation in many different organ systems, as well as by excessive production of antibodies to nuclear, cytoplasmic an

Claims (76)

WE CLAIM:
1. A method for modulating the release of zinc from metallothionein within a cell comprising altering the concentrations of glutathione and glutathione disulfide within the cell.
2. A method of promoting the release of zinc from metallothionein within a cell comprising increasing the concentration of glutathione disulfide within the cell.
3. A method of promoting the release of zinc from metallothionein within a cell comprising increasing the concentration of glutathione disulfide within the cell in the presence of naturally occurring glutathione.
4. A method of promoting the release of zinc from metallothionein within a cell comprising administering to the cell a zinc-releasing amount of an oxidizing agent.
5. The method according to claim 4 wherein said oxidizing agent is selected from the group consisting of ebselen, selenocystine, selenocystamine, selenoglutathione disulfide, iron(III) chelates, dehydroascorbate, glutathione disulfide, coenzyme A
disulfide, cystamine, FAD, NAD+, copper (II) chelates, and combinations thereof.
6. The method according to claim 4 wherein said oxidizing agent is selected from the group consisting of ebselen, glutathione disulfide, and combinations thereof.
7. The method according to claim 4 wherein said oxidizing agent is ebselen.
8. A method of inhibiting the release of zinc from metallothionein within a cell comprising increasing the concentration of glutathione within the cell.
9. A method of inhibiting the release of zinc from metallothionein within a cell comprising increasing the concentration of glutathione within the cell in the presence of naturally occurring glutathione disulfide.
10. A method of inhibiting the release of zinc from metallothionein within a cell comprising administering to the cell an amount of a reducing agent effective to inhibit the release of zinc from metallothionein.
11. The method according to claim 10 wherein said reducing agent is selected from the group consisting of selenocysteine, selenoglutathione, selenocysteamine, iron(II) chelates, ascorbate, glutathione, coenzyme A, cysteamine, FADH,, NADH, copper(I) chelates, vitamin E, N-acetyl-L-cysteine, .alpha.-lipoate, and combinations thereof.
12. The method according to claim 10 wherein said reducing agent is selected from the group consisting of glutathione, ascorbate, vitamin E, and combinations thereof.
13. The method according to claim 1 wherein said cell is a cultured cell.
14. The method according to claim 1 wherein said cell is contained in a host organism.
15. The method according to claim 14 wherein said organism is a plant.
16. The method according to claim 14 wherein said organism is an animal.
17. The method according to claim 16 wherein said animal is a human.
18. A method of treating a subject having a pathological condition in which zinc homeostasis is perturbed, comprising administering to the subject an amount of a compound effective to treat said condition, wherein said compound changes the cellular oxidation state to effect an action selected from the group consisting of causing a release of zinc from metallothionein and preventing release of zinc from metallothionein.
19. The method according to claim 18 wherein said compound is selected from the group consisting of ebselen, cytochrome c, ascorbate, dehydroascorbate, glutathione, glutathione disulfide, coenzyme A, cystamine, cysteamine, FAD, FADH2, azurin, vitamin E, N-acetyl-1,-cysteine, .alpha.-lipoate, and combinations thereof.
20. The method according to claim 18 wherein said compound is ebselen, ascorbate, dehydroascorbate, glutathione, glutathione disulfide, cystamine, cysteamine, azurin, vitamin E, N-acetyl-L-cysteine, or .alpha.-lipoate.
21. The method according to claim 18 wherein said compound is ebselen.
22. The method according to claim 18 wherein said pathological condition is a disease of the central nervous system, said method comprising administering to the subject a reducing agent that inhibits release of zinc from metallothionein in an amount effective for treatment of the disease of the central nervous system.
23. The method according to claim 22 wherein said reducing agent is selected from the group consisting of selenocysteine, selenoglutathione, selenocysteamine, iron(II) chelates, ascorbate, glutathione, coenzyme A, cysteamine, FADH2, NADH, copper(I) chelates, vitamin E, N-acetyl-L-cysteine, .alpha.-lipoate, and combinations thereof.
24. The method according to claim 18 wherein said pathological condition is Alzheimer's disease, said method comprising administering to the subject a reducing agent that inhibits release of zinc from metallothionein in an amount effective for treatment of the Alzheimer's disease.
25. The method according to claim 24 wherein said reducing agent is selected from the group consisting of selenocysteine, selenoglutathione, selenocysteamine, iron(II) chelates, ascorbate, glutathione, coenzyme A, cysteamine, FADH2, NADH, copper(I) chelates, vitamin E, N-acetyl-L-cysteine, .alpha.-lipoate, and combinations thereof.
26. The method according to claim 18 wherein said pathological condition is a neurodegenerative disease, said method comprising administering to the subject a reducing agent that inhibits release of zinc from metallothionein in an amount effective for treatment of the neurodegenerative disease.
27. The method according to claim 26 wherein said neurodegenerative disease is selected from the group consisting of Parkinson's disease, and amyotrophic lateral sclerosis.
28. The method according to claim 26 wherein said reducing agent is selected from the group consisting of selenocysteine, selenoglutathione, selenocysteamine, iron(II) chelates, ascorbate, glutathione, coenzyme A, cysteamine, FADH2, NADH, copper(I) chelates, vitamin E, N-acetyl-L-cysteine, .alpha.-lipoate, and combinations thereof.
29. The method according to claim 18 wherein said pathological condition is epilepsy, said method comprising administering to the subject a reducing agent that inhibits release of zinc from metallothionein in an amount effective for treatment of the epilepsy.
30. The method according to claim 29 wherein said reducing agent is selected from the group consisting of selenocysteine, selenoglutathione, selenocysteamine, iron(II) chelates, ascorbate, glutathione, coenzyme A, cysteamine, FADH2, NADH, copper(I) chelates, vitamin E, N-acetyl-L-cysteine, .alpha.-lipoate, and combinations thereof.
31. A The method according to claim 18 wherein said pathological condition is a drug or alcohol addiction, said method comprising administering to the subject an oxidizing agent that promotes release of zinc from metallothionein in an amount effective for treatment of the addiction.
32. The method according to claim 31 wherein said oxidizing agent is selected from the group consisting of ebselen, selenocystine, selenocystamine, selenoglutathione disulfide, iron(III) chelates, dehydroascorbate, glutathione disulfide, coenzyme A
disulfide, cystamine, FAD, NAD+, copper (II) chelates, and combinations thereof.
33. The method according to claim 18 wherein said pathological condition is a severe mental illness, said method comprising administering to the subject an oxidizing agent that promotes release of zinc from metallothionein in an amount effective for treatment of the severe mental illness.
34. The method according to claim 33 wherein said severe mental illness is selected from the group consisting of depression and schizophrenia.
35. The method according to claim 33 wherein said oxidizing agent is selected from the group consisting of ebselen, selenocystine, selenocystamine, selenoglutathione disulfide, iron(III) chelates, dehydroascorbate, glutathione disulfide, coenzyme A
disulfide, cystamine, FAD, NAD+, copper (II) chelates, and combinations thereof.
36. The method according to claim 18 wherein said pathological condition is an eating disorder.
37. The method according to claim 36 wherein said eating disorder is selected from the group consisting of anorexia nervosa, bulimia and obesity.
38. The method according to claim 18 wherein said pathological condition is anorexia nervosa, said method comprising administering to the subject an oxidizing agent that promotes release of zinc from metallothionein in an amount effective for treatment of the anorexia nervosa.
39. The method according to claim 38 wherein said oxidizing agent is selected from the group consisting of ebselen, selenocystine, selenocystamine, selenoglutathione disulfide, iron(III) chelates, dehydroascorbate, glutathione disulfide, coenzyme A
disulfide, cystamine, FAD, NAD+, copper (II) chelates, and combinations thereof.
40. The method according to claim 18 wherein said pathological condition is obesity, said method comprising administering to the subject a reducing agent that inhibits release of zinc from metallothionein in an amount effective for treatment of the obesity.
41. The method according to claim 40 wherein said reducing agent is selected from the group consisting of selenocysteine, selenoglutathione, selenocysteamine, iron(II) chelates, ascorbate, glutathione, coenzyme A, cysteamine, FADH2, NADH, copper(I) chelates, vitamin E, N-acetyl-L-cysteine, .alpha.-lipoate, and combinations thereof.
42. The method according to claim 18 wherein said pathological condition is an inflammatory disease, said method comprising administering to the subject an oxidizing agent that promotes release of zinc from metallothionein in an amount effective for treatment of the inflammatory disease wherein said inflammatory disease is selected from the group consisting of colitis and Crohn's disease.
43. The method according to claim 42 wherein said oxidizing agent is selected from the group consisting of ebselen, selenocystine, selenocystamine, selenoglutathione disulfide, iron(III) chelates, dehydroascorbate, glutathione disulfide, coenzyme A
disulfide, cystamine, FAD, NAD+, copper (II) chelates, and combinations thereof.
44. The method according to claim 18 wherein said pathological condition is a disorder of the endocrine system, said method comprising administering to the subject a reducing agent that inhibits release of zinc from metallothionein in an amount effective for treatment of the disorder of the endocrine system.
45. The method according to claim 44 wherein said reducing agent is selected from the group consisting of selenocysteine, selenoglutathione, selenocysteamine, iron(II) chelates, ascorbate, glutathione, coenzyme A, cysteamine, FADH2, NADH, copper(I) chelates, vitamin E, N-acetyl-L-cysteine, .alpha.-lipoate, and combinations thereof.
46. The method according to claim 44 wherein said disorder of the endocrine system is selected from prostate cancer, prostate hypertrophy, a disorder of the thyroid, a disorder of the ovaries, and a disorder of the adrenal gland.
47. The method according to claim 18 wherein said pathological condition is pathological apoptosis, said method comprising administering to the subject an oxidizing agent that promotes release of zinc from metallothionein in an amount effective for treatment of the pathological apoptosis.
48. The method according to claim 47 wherein said oxidizing agent is selected from the group consisting of ebselen, selenocystine, selenocystamine, selenoglutathione disulfide, iron(III) chelates, dehydroascorbate, glutathione disulfide, coenzyme A
disulfide, cystamine, FAD, NAD+, copper (II) chelates, and combinations thereof.
49. The method according to claim 18 wherein said pathological condition is cancer, said method comprising administering to the subject an oxidizing agent that promotes release of zinc from metallothionein in an amount effective for inducing apoptosis of the cells of the cancer.
50. The method according to claim 49 wherein said oxidizing agent is selected from the group consisting of ebselen, selenocystine, selenocystamine, selenoglutathione disulfide, iron(III) chelates, dehydroascorbate, glutathione disulfide, coenzyme A
disulfide, cystamine, FAD, NAD+, copper (II) chelates, and combinations thereof.
51. The method according to claim 18 wherein said pathological condition is cancer, said method comprising administering to the subject a reducing agent that inhibits release of zinc from metallothionein in an amount effective for inhibiting proliferation of the cells of the cancer.
52. The method according to claim 51 wherein said reducing agent is selected from the group consisting of selenocysteine, selenoglutathione, selenocysteamine, iron(II) chelates, ascorbate, glutathione, coenzyme A, cysteamine, FADH2, NADH, copper(I) chelates, vitamin E, N-acetyl-L-cysteine, .alpha.-lipoate, and combinations thereof.
53. The method according to claim 18 wherein said pathological condition is an autoimmune disease, said method comprising administering to the subject an oxidizing agent that promotes release of zinc from metallothionein in an amount effective for treatment of the autoimmune disease.
54. The method according to claim 53 wherein said oxidizing agent is selected from the group consisting of ebselen, selenocystine, selenocystamine, selenoglutathione disulfide, iron(III) chelates, dehydroascorbate, glutathione disulfide, coenzyme A
disulfide, cystamine, FAD, NAD+, copper (II) chelates, and combinations thereof.
55. The method according to claim 18 wherein said pathological condition is a viral disease.
56. The method according to claim 18 wherein said viral disease is selected from the group consisting of infection by the common cold, HIV, hepatitis C, measles, papilloma, and Semliki Forest virus.
57. The method according to claim 18 wherein said pathological condition is an infection with HIV, said method comprising administering to the subject a reducing agent that inhibits release of zinc from metallothionein in an amount effective for treatment of the infection with HIV.
58. The method according to claim 57 wherein said reducing agent is selected from the group consisting of selenocysteine, selenoglutathione, selenocysteamine, iron(II) chelates, ascorbate, glutathione, coenzyme A, cysteamine, FADH2, NADH, copper(I) chelates, vitamin E, N-acetyl-L-cysteine, .alpha.-lipoate, and combinations thereof.
59. The method according to claim 18 wherein said pathological condition is a plant disease.
60. The method according to claim 59 wherein said plant disease is ilarvirus or mosaic virus, said method comprising administering to the subject a reducing agent that inhibits release of zinc from metallothionein amount effective for treatment of the infection with the ilarvirus or the mosaic virus.
61. The method according to claim 60 wherein said reducing agent is selected from the group consisting of selenocysteine, selenoglutathione, selenocysteamine, iron(II) chelates, ascorbate, glutathione, coenzyme A, cysteamine, FADH2, NADH, copper(I) chelates, vitamin E, N-acetyl-L-cysteine, .alpha.-lipoate, and combinations thereof.
62. The method according to claim 18 wherein said pathological condition is infection with papilloma virus, said method comprising administering to the subject an oxidizing agent that promotes release of zinc from metallothionein in an amount effective for treatment of the papilloma virus infection.
63. The method according to claim 62 wherein said oxidizing agent is selected from the group consisting of ebselen, selenocystine, selenocystamine, selenoglutathione disulfide, iron(III) chelates, dehydroascorbate, glutathione disulfide, coenzyme A
disulfide, cystamine, FAD, NAD+, copper (II) chelates, and combinations thereof.
64. The method according to claim 18 wherein said pathological condition is infection with hepatitis C virus, said method comprising administering to the subject a reducing agent that inhibits release of zinc from metallothionein in an amount effective for treatment of the hepatitis C virus infection.
65. The method according to claim 64 wherein said reducing agent is selected from the group consisting of selenocysteine, selenoglutathione, selenocysteamine, iron(II) chelates, ascorbate, glutathione, coenzyme A, cysteamine, FADH2, NADH, copper(I) chelates, vitamin E, N-acetyl-L-cysteine, .alpha.-lipoate, and combinations thereof.
66. The method according to claim 18 further comprising co-administering a cofactor selected from the group consisting of glutathione, ATP and GTP.
67. The method according to claim 18 wherein said compound is combined with one or more ingredients selected from the group consisting of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, a wetting agent, a buffering agent, an emulsifying agent, and a binding agent.
68. The method according to claim 18 wherein said compound is formulated as a pharmaceutically acceptable salt.
69. The method according to claim 18 wherein said compound is purified.
70. The method according to claim 18 further comprising coadministering with said compound an amount of purified metallothionein or a derivative thereof.
71. The method according to claim 70 wherein a metallothionein derivative is coadministered, said derivative being bound to an antibody to a cellular antigen.
72. The method according to claim 18 wherein said compound is adapted for intravenous administration to human beings.
73. A pharmaceutical composition comprising purified glutathione in combination with a purified compound selected from the group consisting of ebselen, cytochrome c, ascorbate, dehydroascorbate, glutathione disulfide, coenzyme A, cystamine, cysteamine, FAD, FADH2, azurin, vitamin E, N-acetyl-L-cysteine, .alpha.-lipoate, and combinations thereof.
74. A kit comprising in one or more containers purified glutathione and a purified compound selected from the group consisting of cytochrome c, ascorbate, glutathione, glutathione disulfide, coenzyme A, cystamine, cysteamine, FAD, FADH2, azurin, N-acetyl-L-cysteine, .alpha.-lipoate, and combinations thereof, in an amount effective to modulate the release of zinc from metallothionein.
75. A kit comprising in one or more containers a purified compound selected from the group consisting of cytochrome c, glutathione, glutathione disulfide, coenzyme A, cystamine, cysteamine, FAD, FADH2, azurin, N-acetyl-L-cysteine, .alpha.-lipoate, and combinations thereof, in an amount effective to modulate the release of zinc from metallothionein.
76. The method according to claim 18 wherein said compound is formulated as a suppository.
CA002326771A 1998-03-30 1999-03-29 Agents and methods for modulation of zinc transfer by metallothionein Abandoned CA2326771A1 (en)

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