Glutathione deficiency produced by inhibition of its synthesis, and its reversal; Applications in research and therapy

doi:10.1016/0163-7258(91)90076-X

Pharmacology & Therapeutics

Volume 51, Issue 2, 1991, Pages 155-194

https://doi.org/10.1016/0163-7258(91)90076-X Get rights and content

Abstract

Glutathione, which is synthesized within cells, is a component of a pathway that uses NADPH to provide cells with their reducing milieu. This is essential for (a) maintenance of the thiols of proteins (and other compounds) and of antioxidants (e.g. ascorbate, α-tocopherol), (b) reduction of ribonucleotides to form the deoxyribonucleic precursors of DNA, and (c) protection against oxidative damage, free radical damage, and other types of toxicity. Glutathione interacts with a wide variety of drugs. Despite its many and varied cellular functions, it is possible to achieve therapeutically useful modulations of glutathione metabolism.

This article emphasizes an approach in which the synthesis of glutathione is selectively inhibited in vivo leading to glutathione deficiency. This is achieved through use of transition-state inactivators of γ-glutamylcysteine synthetase, the enzyme that catalyzes the first and rate-limiting step of glutathione synthesis. The effects of marked glutathione deficiency, thus produced in the absence of applied stress, include cellular damage associated with severe mitochondrial degeneration in a number of tissues. Such glutathione deficiency is not prevented or reversed by giving glutathione. The cellular utilization of GSH involves its extracellular degradation, uptake of products, and intracellular synthesis of GSH. This is a normal pathway by which cysteine moieties are taken up by cells. Glutathione deficiency induced by inhibition of its synthesis may be prevented or reversed by administration of glutathione esters which, in contrast to glutathione, are readily transported into cells and hydrolyzed to form glutathione intracellularly.

Research derived from this model has led to several potentially useful therapeutic approaches, one of which is currently in clinical trial. Thus, certain tumors, including those that exhibit resistance to several drugs and to radiation, are sensitized to these modalities by selective inhibition of glutathione synthesis. An alternative interpretation is suggested which is based on the concept that some resistant tumors have high capacity for glutathione synthesis and that such increased capacity may be as significant or more significant in promoting the resistance of some tumors than the cellular levels of glutathione.

Therapeutic approaches are proposed in which normal cells may be selectively protected against toxic antitumor agents and radiation by cysteine- and glutathione-delivery compounds. Current studies suggest that research on other modulations of glutathione metabolism and transport would be of interest.

References (317)

S. Ahmad et al.
Hepatic-mediated elevation and maintenance of metastatic tumor cell glutathione
Biochem. Pharmac.
(1986)
R.D. Allison et al.
Function of γ-glutamyl transpeptidase
J. biol. Chem.
(1981)
M.W. Anders
Inhibition and enhancement of microsomal drug metabolism by diethyl maleate
Biochem. Pharmac.
(1978)
M.E. Anderson et al.
Dynamic state of glutathione in blood plasma
J. biol. Chem.
(1980)
M.E. Anderson et al.
Intracellular delivery of cysteine
Meth. Enzym.
(1987)
M.E. Anderson et al.
Glutathione monoesters
Analyt. Biochem.
(1989)
M.E. Anderson et al.
Direct evidence for inter-organ transport of glutathione and that the non-filtration renal mechanism for glutathione utilization involves γ-glutamyl transpeptidase
Biochem. biophys. Res. Commun.
(1980)
M.E. Anderson et al.
Glutathione monoethyl ester; preparation, uptake by tissues, and conversion to glutathione
Archs. Biochem. Biophys.
(1985)
M.D. Armstrong
The occurrence of cystinylglycine in blood plasma
Biochim. biophys. Acta
(1979)
B.A. Arrick et al.
Glutathione depletion sensitizes tumor cells to oxidative cytolysis
J. biol. Chem.
(1982)

M.B. Astor et al.

Relationship between intracellular glutathione levels and hypoxic cell radiosensitivity

Pharmac. Ther.

(1988)

J.G. Bellows et al.

Alloxan diabetes and the lens

Am. J. Ophthal.

(1950)

M. Berggren et al.

Glutathione biosynthesis in the isolated perfused rat lung: Utilization of extracellular glutathione

FEBS Letts.

(1984)

J.E. Biaglow et al.

The effect of l-buthionine sulfoximine on the aerobic radiation response of A549 human lung carcinoma cells

Int. J. Radiat. Oncol. Biol. Phys.

(1986)

S.M. Birnbaum et al.

Quantitative nutritional studies with water-soluble, chemically defined diets. III. Individual amino acids as sources of “non-essential” nitrogen

Archs Biochem. Biophys.

(1957)

K. Bloch

The synthesis of glutathione in isolated liver

J. biol. Chem.

(1949)

H. Borsook et al.

The oxidation of ascorbic acid and its reduction in vitro and in vivo

J. biol. Chem.

(1937)

R.J. Bridges et al.

γ-Glutamyl amino acids; Transport and conversion to 5-oxoproline in kidney

J. biol. Chem.

(1985)

A.E. Brodie et al.

Buthionine sulfoximine inhibition of cystine uptake and glutathione biosynthesis in human lung carcinoma cells

Toxic. appl. Pharmac.

(1985)

E.A. Bump et al.

Role of glutathione in the radiation response of mammalian cells in vitro and in vivo

Pharmac. Ther.

(1990)

G. Calcutt et al.

Tumor sulphydryl levels and sensitivity to the nitrogen mustard merophan

Biochem. Pharmac.

(1963)

E.P. Clark

Session II: Keynote Address, Thiol-induced biochemical modification of chemo- and radio-responses

Int. J. Radiat. Oncol. biol. Phys.

(1986)

E.E. Conn et al.

Glutathione reductase of wheat germ

J. biol. Chem.

(1951)

T.A. Connors

Protection against the toxicity of alkylating agents by thiols: The mechanism of protection and its relevance to cancer chemotherapy. A review

Eur. J. Cancer

(1966)

A.J.L. Cooper et al.

Enzymatic reactions of methionine sulfoximine, conversion to the corresponding α-imino and α-keto acids, and to α-ketobutyrate and methane sulfinimide

J. biol. Chem.

(1976)

A.J.L. Cooper et al.

On the chemistry and biochemistry of 3-mercaptopyruvic acid, the α-keto acid analog of cysteine

J. biol. Chem.

(1982)

L.G. Costa et al.

Effect of diethyl-maleate and other glutathione depletors on protein synthesis

Biochem. Pharmac.

(1986)

H.D. Dakin et al.

An enzyme concerned with the formation of hydroxy acids from ketonic anhydrides

J. biol. Chem.

(1913)

H.D. Dakin et al.

On glyoxalase

J. biol. Chem.

(1913)

H.D. Dakin et al.

Glyoxalase. Part III. The distribution of the enzyme and its relation to the pancreas

J. biol. Chem.

(1913)

H.H. Debey et al.

3he replacement by thiazolidinecarbozylic acid of exogenous cysteine and cysteine

J. Nutr.

(1958)

L.A. Dethlefsen et al.

Toxic effects of extended glutathione depletion by buthionine sulfoximine on murine mammary carcinoma cells

J. Radiat. Oncol. biol. Phys.

(1986)

T. Doba et al.

Antioxidant and co-antioxidant activity of vitamin C. The effect of vitamin C, either alone or in the presence of vitamin E or a water-soluble vitamin E analogue, upon the peroxidation of aqueous multilamellar phospholipid liposomes

Biochim. biophys. Acta

(1985)

J.H. Doroshow et al.

Role of the glutathione-glutathione peroxidase cycle in the cytotoxicity of the anticancer quinones

Pharmac. Ther.

(1990)

G.W. Douglas et al.

The rate of metabolism of brain and liver glutathione in the rat studied with C¹⁴-glycine

J. biol. Chem.

(1956)

R. Drew et al.

The effects of buthionine sulphoximine on glutathione depletion and xenobiotic biotransformation

Biochem. Pharmac.

(1984)

M.C. Fonteles et al.

Extraction of glutathione by the isolated perfused rabbit kidney

J. surg. Res.

(1976)

H.J. Forman et al.

Superoxide radical and hydrogen peroxide in mitochondria

T. Furukawa et al.

Reversal of age-associated decline in immune responsiveness by dietary glutathione supplementation in mice

Mechanisms of Ageing and Development

(1987)

O.W. Griffith

l-Buthionine-SR-sulfoximine: Mechanism of action, resolution of diastereomers and use as a chemotherapeutic agent

O.W. Griffith et al.

Differential inhibition of glutamine and γ-glutamycysteine synthetases by α-alkyl analogs of methionine sulfoximine that induce convulsions

J. biol. Chem.

(1978)

O.W. Griffith et al.

Potent and specific inhibition of glutathione synthesis by buthionine sulfoximine (S-n-butyl homocysteine sulfoximine)

J. biol. Chem.

(1979)

W.A. Abbott et al.

Intrahepatic transport and utilization of biliary glutathione and its metabolites

W.A. Abbott et al.

Extracellular metabolism of glutathione accounts for its disappearance from the basolateral circulation of the kidney

J. biol. Chem.

(1984)

W.A. Abbott et al.

γ-Glutamyl-glutathione; natural occurrence and enzymology

J. biol. Chem.

(1986)

S. Ahmad et al.

Elevation of glutathione in phenylalanine mustard-resistant murine L1210 leukemia cells

J. biol. Chem.

(1987)

H.P.T. Ammon et al.

Pharmacokinetics of intravenously administered glutathione in the rat

J. Pharm. Pharmac.

(1986)

M.E. Anderson et al.

Transport and direct utilization of γ-glutamylcyst(e)ine for glutathione synthesis

M.E. Anderson et al.

Inhibition of γ-glutamyl transpeptidase and glutathionuria produced by γ-glutamyl amino acids

M.E. Anderson et al.

Marked increase of cysteine levels in many regions of brain after administration of 2-oxothiazolidine-4-carboxylate

FASEB J.

(1989)

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Glutathione deficiency produced by inhibition of its synthesis, and its reversal; Applications in research and therapy

Abstract

Biochem. Pharmac.

J. biol. Chem.

Biochem. Pharmac.

J. biol. Chem.

Meth. Enzym.

Analyt. Biochem.

Biochem. biophys. Res. Commun.

Archs. Biochem. Biophys.

Biochim. biophys. Acta

J. biol. Chem.

Pharmac. Ther.

Am. J. Ophthal.

FEBS Letts.

Int. J. Radiat. Oncol. Biol. Phys.

Archs Biochem. Biophys.

J. biol. Chem.

J. biol. Chem.

J. biol. Chem.

Toxic. appl. Pharmac.

Pharmac. Ther.

Biochem. Pharmac.

Int. J. Radiat. Oncol. biol. Phys.

J. biol. Chem.

Eur. J. Cancer

J. biol. Chem.

J. biol. Chem.

Biochem. Pharmac.

J. biol. Chem.

J. biol. Chem.

J. biol. Chem.

J. Nutr.

J. Radiat. Oncol. biol. Phys.

Biochim. biophys. Acta

Pharmac. Ther.

J. biol. Chem.

Biochem. Pharmac.

J. surg. Res.

Mechanisms of Ageing and Development

J. biol. Chem.

J. biol. Chem.

Intrahepatic transport and utilization of biliary glutathione and its metabolites

Extracellular metabolism of glutathione accounts for its disappearance from the basolateral circulation of the kidney

J. biol. Chem.

γ-Glutamyl-glutathione; natural occurrence and enzymology

J. biol. Chem.

Elevation of glutathione in phenylalanine mustard-resistant murine L1210 leukemia cells

J. biol. Chem.

Pharmacokinetics of intravenously administered glutathione in the rat

J. Pharm. Pharmac.

Transport and direct utilization of γ-glutamylcyst(e)ine for glutathione synthesis

Inhibition of γ-glutamyl transpeptidase and glutathionuria produced by γ-glutamyl amino acids

Marked increase of cysteine levels in many regions of brain after administration of 2-oxothiazolidine-4-carboxylate

FASEB J.