Interaction of the antitumor drug, L‐(α<i>S</i>, 5<i>S</i>)‐α‐amino‐3‐chloro‐4,5‐dihydro‐5‐isoxazoleacetic acid (AT‐125) with renal brush border membranes

Kozak, Elena; Tate, Suresh S.

doi:10.1016/0014-5793(80)80431-5

Cited by 34 publications

(7 citation statements)

References 19 publications

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“…was substantial labeling of the plasma membrane proteins, a result different from that found (31) in studies on the renal brush border. Serine + borate did not inhibit transport ofglutathione in HSB or CEM cells.…”

Section: Discussioncontrasting

confidence: 53%

Glutathione export by human lymphoid cells: depletion of glutathione by inhibition of its synthesis decreases export and increases sensitivity to irradiation.

Dethmers¹,

Meister²

1981

Proc. Natl. Acad. Sci. U.S.A.

181

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Glutathione (in the form of GSH) is transported out of cultured human lymphoid cells at rates proportional to the intracellular glutathione levels. Inhibition ofglutathione synthesis by buthionine sulfoximine, a potent selective inhibitor of Y-glutamylcysteine synthetase, leads to exponential decrease in intracellular glutathione, a large fraction of which appears extracellularly, indicating that glutathione turnover is associated with its export. Although cells with 0.09 mM glutathione (4% of controls) were 85% viable; further decrease was associated with marked loss of viability. Cells with 4-5% of control glutathione levels were much more sensitive than control cells to the effects of y radiation and of5,5'-dithiobis(2-nitrobenzoate). Depletion ofglutathione by use of buthionine sulfoximine has advantages over other reagents (such as diamide, other oxidizing agents, and diethylmaleate, which affect other cellular components and may increase glutathione disulfide levels) and therefore has potential usefulness in sensitizing cells to the.effects ofradiation and to therapeutic agents that are detoxified by reactions involving glutathione.

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Section: Discussioncontrasting

confidence: 53%

Glutathione export by human lymphoid cells: depletion of glutathione by inhibition of its synthesis decreases export and increases sensitivity to irradiation.

Dethmers¹,

Meister²

1981

Proc. Natl. Acad. Sci. U.S.A.

181

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“…Acivicin (AT-125; 224, Figure 20), an irreversible inhibitor of GGT, is a fermentation product of Streptomyces sviceus (Martin et al 1973). Several early studies showed that acivicin (224, Figure 20) inhibits mammalian GGT (Allen et al 1980;Gardell and Tate 1980;Kozak and Tate 1980;Reed et al 1980). Studies also showed that acivicin (224, Figure 20) exhibited antitumor properties in tumor-derived cell lines and in experimental animals (Allen et al 1980;Thornthwaite and Allen 1980;Poster et al 1981;Lui et al 1982;Weber et al 1982).…”

Section: Irreversible Inhibitors Azaserine (222 Figurementioning

confidence: 99%

“…Acivicin (224, Figure 20) stoichiometrically and covalently reacts with purified rat kidney GGT and is a more effective inhibitor of the enzyme than DON (Gardell and Tate 1980); L-Ser-borate, a transition-state inhibitor of GGT, protects against acivicin-induced inhibition. Although acivicin (224, Figure 20) inhibits several enzymes that utilize L-Gln as a substrate (Ahluwalia et al 1990;Pinto et al 2016), only GGT appears to be covalently modified by [2-3 H]acivicin in rat renal brush-border membranes (Kozak and Tate 1980). Mutations S451A and S452A caused a drastic reduction in the acivicin-induced hGGT inactivation rates; Ser451 and Ser452 were suggested to be potential active-site nucleophiles (Ikeda et al 1995).…”

Section: Irreversible Inhibitors Azaserine (222 Figurementioning

confidence: 99%

The mercapturic acid pathway

Hanna

Anders

2019

Critical Reviews in Toxicology

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The mercapturic acid pathway is a major route for the biotransformation of xenobiotic and endobiotic electrophilic compounds and their metabolites. Mercapturic acids (N-acetyl-L-cysteine S-conjugates) are formed by the sequential action of the glutathione transferases, c-glutamyltransferases, dipeptidases, and cysteine S-conjugate N-acetyltransferase to yield glutathione S-conjugates, L-cysteinylglycine S-conjugates, L-cysteine S-conjugates, and mercapturic acids; these metabolites constitute a "mercapturomic" profile. Aminoacylases catalyze the hydrolysis of mercapturic acids to form cysteine S-conjugates. Several renal transport systems facilitate the urinary elimination of mercapturic acids; urinary mercapturic acids may serve as biomarkers for exposure to chemicals. Although mercapturic acid formation and elimination is a detoxication reaction, L-cysteine S-conjugates may undergo bioactivation by cysteine Sconjugate b-lyase. Moreover, some L-cysteine S-conjugates, particularly L-cysteinyl-leukotrienes, exert significant pathophysiological effects. Finally, some enzymes of the mercapturic acid pathway are described as the so-called "moonlighting proteins," catalytic proteins that exert multiple biochemical or biophysical functions apart from catalysis.

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“…y-Glutamyl transpeptidase (y-GT) is reported to be a membranebound enzyme (4,10,15) that catalyzes the transfer of y-glutamyl moieties to the amino acids (18). It has also been found to take part in detoxification of ammonia in the kidney (16), in production of leukouiene (20,22), and to have co-enzyme activity (17).…”

Section: Introductionmentioning

confidence: 99%

Distribution of gamma-glutamyl transpeptidase in human salivary glands: immunohistochemical study using a monoclonal antibody.

Shiozawa

Yasuda

Yamashita

et al. 1993

J Histochem Cytochem.

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We studied in detail the distribution pattern of gamma-glutamyl transpeptidase (gamma-GT) in human salivary glands using a monoclonal antibody (MAb) to human kidney gamma-GT. In the sublingual gland, a strong reactivity of the enzyme was recognized along the luminal and lateral membranes of serous cells. Weak but positive reactivity was noted on the luminal membrane of mucous cells. The intercellular canaliculi in the demilune and luminal surfaces of excretory duct cells were also immunoreactive. In the submandibular gland, a weak reaction was observed on the luminal membrane of intercalated duct cells and striated duct cells. Faint reactivity was seen on the luminal membrane of striated duct cells of the parotid gland. No reaction was observed in serous cells of the parotid gland. The immunoreaction in the sublingual gland was stronger than that in submandibular or parotid glands.

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Interaction of the antitumor drug, L‐(αS, 5S)‐α‐amino‐3‐chloro‐4,5‐dihydro‐5‐isoxazoleacetic acid (AT‐125) with renal brush border membranes

Cited by 34 publications

References 19 publications

Glutathione export by human lymphoid cells: depletion of glutathione by inhibition of its synthesis decreases export and increases sensitivity to irradiation.

Glutathione export by human lymphoid cells: depletion of glutathione by inhibition of its synthesis decreases export and increases sensitivity to irradiation.

The mercapturic acid pathway

Distribution of gamma-glutamyl transpeptidase in human salivary glands: immunohistochemical study using a monoclonal antibody.

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