Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1988-03-07
1990-05-22
Lee, Lester L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 18, 530330, 530331, 560147, A61K 3702, C07K 506, C07K 510
Patent
active
049278088
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to .gamma.Y-L-glutamyl-L-cysteine ethyl ester and agents to increase the tissue glutathione levels, medicines for liver diseases, drugs for cataract, and medicines for kidney diseases, which contain the same as an effective ingredient.
TECHNICAL BACKGROUND
Glutathione is present in almost all biological tissues as a major intracellular reducing agent and plays important roles in catalysis, metabolism, transport and protection of cells. To be particular as to the protection of cells, glutathione displays said function (1) by reductively destorying reactive oxygen compounds and free radicals with the acid of glutathione peroxidase or (2) by reacting with intracellular toxic compound with the aid of glutathione-S-transferase and the reaction product being excreted out of the cells as a glutathione conjugate, thus playing roles in antioxidation, detoxication, protection against radiation injury, and increasing resistance to temperature, etc.
Therefore, when the tissue content of glutathione has decreased due to diseases or aging, the tissue becomes liable to suffer injuries. It is important for the restoration of lost cellular functions to decreased tissue glutathione levels to the normal value and it is also generally regarded that the cellular protective function can be further enhanced by increasing the tissue glutathione even in case of a normal cell. Actually it has also been reported that glutathione and several kinds of thiol compounds were used effective in protecting against mutagenic and carcinogenic substances and further in reducing the tumor size of the animal liver caused by from said malignant substances.
However, there are problems that half life of glutathione in blood is short (several minutes) and administration of glutathione itself is not so useful in increasing tisse glutathione. It is considered that this is due to the facts that glutathione itself can not be taken efficiently into cells, and exogenously supplied glutathione must be once degraded to its constituent peptide or amino acids, which are able to be transported and converted intracellularly to glutathione.
There have been several compounds that overcome problems above-mentioned and are proved to be superior to glutathione in increasing glutathione level of human lymphoma cells or animal tissues. 2-oxothiazolidine-4-carboxylate, .gamma.-L-glutamyl-L-cysteine, and r-L-glutamyl-L-cysteinyl-glycine ethyl ester (glutathione monoethyl ester), etc. (for instance, Curr. Top. Cell. Regul., vol. 26, pp 383-394, 1985; Fed. Proc., vol. 43, pp 3031-3043, 1984).
Disclosure of the Invention
The present inventors have made a search for new compounds, which are effective for increasing glutathione in the tissue, by using a primary cultured hepatoxyte and found that .gamma.-L-glutamyl-L-cysteine ethyl ester is effective in increasing glutathione of the liver cells; that especially in case where glutathione level is decreased by use of D,L-buthionine-sulfoximine, an inhibitor of glutathione synethesis, the addition of said glutamyl compound after the removal of the inhibitor makes the glutathione level recover at a remarkably high speed; that the glutathione level recovering effect of this compound is much superior to the compounds previously mentioned in the preceding paragraph; and that the compound prevents the necrosis of liver cells due to carbon tetrachloride treatment, thus achieved the present invention.
More particularly, this invention relates to .gamma.-L-glutamyl-L-cysteine ethyl ester represented by the following formula ##STR1## and agents to increase the tissue glutathione levels, medicines for liver diseases, drugs for cataract, and medicines for renal diseases, which contain the same as an effective ingredient.
The aforementioned formula indicates compound of reduced form and oxidized form of .gamma.-L-glutamyl-L-cysteine ethyl ester (oxidized type dimer), which is a dimer comprising a disulfide linkage (-S-S-) formed by the dehydrogenation reaction caused between the two molec
REFERENCES:
patent: 4596775 (1986-06-01), Kimura et al.
patent: 4598046 (1986-07-01), Kimura et al.
patent: 4710489 (1987-12-01), Meister
Flohe et al., The Identity of Glutatione Peroxidase from Erythocytes and Liver of the Rat, Z. Klin, Chem. 4, Klin Biochem. vol. 8, (1970), pp. 149-155.
Anderson et al., Glutathione Monoethyl Ester: Preparation, Uptake by Tissues, and Conversion to Glutathione, Arch. Biochem. Biophys., vol. 239, No. 2, pp. 538-548.
Fujii Katsuhiko
Kitahara Shigehisa
Ohtsu Akira
Lee Lester L.
Teijin Limited
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