Influence of pH on the modification of thiols by carbamoylating agents and effects on glutathione levels in normal and neoplastic cells

Jennifer Hu, Michele J. Dimaira, Karimullah A. Zirvi, George Dikdan, Michael A. Lea

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

In previous studies, we have suggested that the selective inhibitory effect of sodium cyanate (NaOCN) on hepatoma metabolism may be due to the lower pH observed in tumors relative to normal tissues. Lower pH might enhance the action of NaOCN by increasing the formation of isocyanic acid and carbamoylation of sulfhydryl groups. In the present work, studies were conducted on the effect of pH on the carbamoylation of sulfhydryl groups. The data indicated that carbamoylation of the sulfhydryl group of glutathione by NaOCN was enhanced by decreasing the pH from 7.4 to 6.6. A less pH-dependent response was observed with organic isocyanates. However, all reactions were reversible after the pH was increased by the addition of base. Kinetic studies showed that the rate of the reaction is very rapid, a maximal effect occurring within the first 10 min. Dose-dependent modifications of cellular glutathione by NaOCN and organic isocyanates were observed in human HT29 colon tumor cells, rat HTC hepatoma cells, and rat hepatocytes. The rate of carbamoylation of the glutathione sulfhydryl group in cells was similar to that of pure glutathione (GSH). The effect of buthionine sulfoximine on GSH levels in cells was at least as great as that of sodium cyanate, but only the latter showed inhibitory effects on macromolecular synthesis; these were very rapid, pH-dependent, and reversible in tumor cells. Our results suggest that cellular sulfhydryl group(s) other than that of GSH might be involved in the effect of NaOCN on macromolecular synthesis.

Original languageEnglish
Pages (from-to)95-101
Number of pages7
JournalCancer Chemotherapy and Pharmacology
Volume24
Issue number2
DOIs
StatePublished - Aug 1 1989
Externally publishedYes

Fingerprint

Sulfhydryl Compounds
Glutathione
Isocyanates
Tumors
Rats
Cells
Buthionine Sulfoximine
Hepatocellular Carcinoma
Metabolism
Neoplasms
Tissue
Kinetics
Hepatocytes
Colon
sodium cyanate

ASJC Scopus subject areas

  • Pharmacology
  • Oncology
  • Cancer Research

Cite this

Influence of pH on the modification of thiols by carbamoylating agents and effects on glutathione levels in normal and neoplastic cells. / Hu, Jennifer; Dimaira, Michele J.; Zirvi, Karimullah A.; Dikdan, George; Lea, Michael A.

In: Cancer Chemotherapy and Pharmacology, Vol. 24, No. 2, 01.08.1989, p. 95-101.

Research output: Contribution to journalArticle

Hu, Jennifer ; Dimaira, Michele J. ; Zirvi, Karimullah A. ; Dikdan, George ; Lea, Michael A. / Influence of pH on the modification of thiols by carbamoylating agents and effects on glutathione levels in normal and neoplastic cells. In: Cancer Chemotherapy and Pharmacology. 1989 ; Vol. 24, No. 2. pp. 95-101.
@article{d0c9906bad0449ab91dd2d4ccd1ada84,
title = "Influence of pH on the modification of thiols by carbamoylating agents and effects on glutathione levels in normal and neoplastic cells",
abstract = "In previous studies, we have suggested that the selective inhibitory effect of sodium cyanate (NaOCN) on hepatoma metabolism may be due to the lower pH observed in tumors relative to normal tissues. Lower pH might enhance the action of NaOCN by increasing the formation of isocyanic acid and carbamoylation of sulfhydryl groups. In the present work, studies were conducted on the effect of pH on the carbamoylation of sulfhydryl groups. The data indicated that carbamoylation of the sulfhydryl group of glutathione by NaOCN was enhanced by decreasing the pH from 7.4 to 6.6. A less pH-dependent response was observed with organic isocyanates. However, all reactions were reversible after the pH was increased by the addition of base. Kinetic studies showed that the rate of the reaction is very rapid, a maximal effect occurring within the first 10 min. Dose-dependent modifications of cellular glutathione by NaOCN and organic isocyanates were observed in human HT29 colon tumor cells, rat HTC hepatoma cells, and rat hepatocytes. The rate of carbamoylation of the glutathione sulfhydryl group in cells was similar to that of pure glutathione (GSH). The effect of buthionine sulfoximine on GSH levels in cells was at least as great as that of sodium cyanate, but only the latter showed inhibitory effects on macromolecular synthesis; these were very rapid, pH-dependent, and reversible in tumor cells. Our results suggest that cellular sulfhydryl group(s) other than that of GSH might be involved in the effect of NaOCN on macromolecular synthesis.",
author = "Jennifer Hu and Dimaira, {Michele J.} and Zirvi, {Karimullah A.} and George Dikdan and Lea, {Michael A.}",
year = "1989",
month = "8",
day = "1",
doi = "10.1007/BF00263127",
language = "English",
volume = "24",
pages = "95--101",
journal = "Cancer Chemotherapy and Pharmacology",
issn = "0344-5704",
publisher = "Springer Verlag",
number = "2",

}

TY - JOUR

T1 - Influence of pH on the modification of thiols by carbamoylating agents and effects on glutathione levels in normal and neoplastic cells

AU - Hu, Jennifer

AU - Dimaira, Michele J.

AU - Zirvi, Karimullah A.

AU - Dikdan, George

AU - Lea, Michael A.

PY - 1989/8/1

Y1 - 1989/8/1

N2 - In previous studies, we have suggested that the selective inhibitory effect of sodium cyanate (NaOCN) on hepatoma metabolism may be due to the lower pH observed in tumors relative to normal tissues. Lower pH might enhance the action of NaOCN by increasing the formation of isocyanic acid and carbamoylation of sulfhydryl groups. In the present work, studies were conducted on the effect of pH on the carbamoylation of sulfhydryl groups. The data indicated that carbamoylation of the sulfhydryl group of glutathione by NaOCN was enhanced by decreasing the pH from 7.4 to 6.6. A less pH-dependent response was observed with organic isocyanates. However, all reactions were reversible after the pH was increased by the addition of base. Kinetic studies showed that the rate of the reaction is very rapid, a maximal effect occurring within the first 10 min. Dose-dependent modifications of cellular glutathione by NaOCN and organic isocyanates were observed in human HT29 colon tumor cells, rat HTC hepatoma cells, and rat hepatocytes. The rate of carbamoylation of the glutathione sulfhydryl group in cells was similar to that of pure glutathione (GSH). The effect of buthionine sulfoximine on GSH levels in cells was at least as great as that of sodium cyanate, but only the latter showed inhibitory effects on macromolecular synthesis; these were very rapid, pH-dependent, and reversible in tumor cells. Our results suggest that cellular sulfhydryl group(s) other than that of GSH might be involved in the effect of NaOCN on macromolecular synthesis.

AB - In previous studies, we have suggested that the selective inhibitory effect of sodium cyanate (NaOCN) on hepatoma metabolism may be due to the lower pH observed in tumors relative to normal tissues. Lower pH might enhance the action of NaOCN by increasing the formation of isocyanic acid and carbamoylation of sulfhydryl groups. In the present work, studies were conducted on the effect of pH on the carbamoylation of sulfhydryl groups. The data indicated that carbamoylation of the sulfhydryl group of glutathione by NaOCN was enhanced by decreasing the pH from 7.4 to 6.6. A less pH-dependent response was observed with organic isocyanates. However, all reactions were reversible after the pH was increased by the addition of base. Kinetic studies showed that the rate of the reaction is very rapid, a maximal effect occurring within the first 10 min. Dose-dependent modifications of cellular glutathione by NaOCN and organic isocyanates were observed in human HT29 colon tumor cells, rat HTC hepatoma cells, and rat hepatocytes. The rate of carbamoylation of the glutathione sulfhydryl group in cells was similar to that of pure glutathione (GSH). The effect of buthionine sulfoximine on GSH levels in cells was at least as great as that of sodium cyanate, but only the latter showed inhibitory effects on macromolecular synthesis; these were very rapid, pH-dependent, and reversible in tumor cells. Our results suggest that cellular sulfhydryl group(s) other than that of GSH might be involved in the effect of NaOCN on macromolecular synthesis.

UR - http://www.scopus.com/inward/record.url?scp=0024323686&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0024323686&partnerID=8YFLogxK

U2 - 10.1007/BF00263127

DO - 10.1007/BF00263127

M3 - Article

C2 - 2731317

AN - SCOPUS:0024323686

VL - 24

SP - 95

EP - 101

JO - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

SN - 0344-5704

IS - 2

ER -