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Effect of thioacetamide on the hepatic expression of gamma-glutamylcysteine synthetase subunits in the Rat.
Toxicol Appl Pharmacol. 1999 Sep 15; 159(3):161-8.TA

Abstract

Glutathione (GSH) is the main nonprotein thiol important in antioxidant defense and maintenance of the intracellular redox state. A major determinant of the rate of GSH synthesis is the activity of the rate-limiting enzyme, gamma-glutamylcysteine synthetase (GCS). A heavy (HS) and light subunit (LS) make up GCS; oxidative stress regulates both transcriptionally. cis-Acting elements important for the oxidative stress-induced transcriptional up-regulation of both subunits are antioxidant response element (ARE) and activator protein-1 (AP-1) site. The nuclear factor-kappaB (NF-kappaB) binding site may also regulate the heavy subunit. Increased GSH and gamma-glutamyltranspeptidase are often observed in preneoplastic hepatocyte nodules and may be important in hepatocarcinogenesis. The current work examined the effect of a commonly used hepatocarcinogen, thioacetamide (TAA), on the expression of GCS subunits. After 3 weeks of TAA treatment, liver GSH level remained unchanged despite significant oxidative stress as measured by the thiobarbituric acid reactive substance assay. The mRNA levels of GCS-HS and GCS-LS increased six- and fourfold, respectively, and the protein level of GCS-HS and GCS activity all increased. Electrophorectic mobility shift assay showed binding to ARE, AP-1, and NF-kappaB probes all increased. These results suggest TAA treatment increased hepatic GCS subunit expression and GCS activity by inducing oxidative stress and increasing the binding to redox-sensitive cis-acting elements important for transcriptional up-regulation of GCS. This is the first in vivo study that examined the effect of a hepatocarcinogen on GCS expression.

Authors+Show Affiliations

USC Liver Disease Research Center, USC School of Medicine, Los Angeles, California, 90033, USA. shellylu@hsc.usc.eduNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

10486302

Citation

Lu, S C., et al. "Effect of Thioacetamide On the Hepatic Expression of Gamma-glutamylcysteine Synthetase Subunits in the Rat." Toxicology and Applied Pharmacology, vol. 159, no. 3, 1999, pp. 161-8.
Lu SC, Huang ZZ, Yang H, et al. Effect of thioacetamide on the hepatic expression of gamma-glutamylcysteine synthetase subunits in the Rat. Toxicol Appl Pharmacol. 1999;159(3):161-8.
Lu, S. C., Huang, Z. Z., Yang, H., & Tsukamoto, H. (1999). Effect of thioacetamide on the hepatic expression of gamma-glutamylcysteine synthetase subunits in the Rat. Toxicology and Applied Pharmacology, 159(3), 161-8.
Lu SC, et al. Effect of Thioacetamide On the Hepatic Expression of Gamma-glutamylcysteine Synthetase Subunits in the Rat. Toxicol Appl Pharmacol. 1999 Sep 15;159(3):161-8. PubMed PMID: 10486302.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of thioacetamide on the hepatic expression of gamma-glutamylcysteine synthetase subunits in the Rat. AU - Lu,S C, AU - Huang,Z Z, AU - Yang,H, AU - Tsukamoto,H, PY - 1999/9/16/pubmed PY - 1999/9/16/medline PY - 1999/9/16/entrez SP - 161 EP - 8 JF - Toxicology and applied pharmacology JO - Toxicol. Appl. Pharmacol. VL - 159 IS - 3 N2 - Glutathione (GSH) is the main nonprotein thiol important in antioxidant defense and maintenance of the intracellular redox state. A major determinant of the rate of GSH synthesis is the activity of the rate-limiting enzyme, gamma-glutamylcysteine synthetase (GCS). A heavy (HS) and light subunit (LS) make up GCS; oxidative stress regulates both transcriptionally. cis-Acting elements important for the oxidative stress-induced transcriptional up-regulation of both subunits are antioxidant response element (ARE) and activator protein-1 (AP-1) site. The nuclear factor-kappaB (NF-kappaB) binding site may also regulate the heavy subunit. Increased GSH and gamma-glutamyltranspeptidase are often observed in preneoplastic hepatocyte nodules and may be important in hepatocarcinogenesis. The current work examined the effect of a commonly used hepatocarcinogen, thioacetamide (TAA), on the expression of GCS subunits. After 3 weeks of TAA treatment, liver GSH level remained unchanged despite significant oxidative stress as measured by the thiobarbituric acid reactive substance assay. The mRNA levels of GCS-HS and GCS-LS increased six- and fourfold, respectively, and the protein level of GCS-HS and GCS activity all increased. Electrophorectic mobility shift assay showed binding to ARE, AP-1, and NF-kappaB probes all increased. These results suggest TAA treatment increased hepatic GCS subunit expression and GCS activity by inducing oxidative stress and increasing the binding to redox-sensitive cis-acting elements important for transcriptional up-regulation of GCS. This is the first in vivo study that examined the effect of a hepatocarcinogen on GCS expression. SN - 0041-008X UR - https://www.unboundmedicine.com/medline/citation/10486302/Effect_of_thioacetamide_on_the_hepatic_expression_of_gamma_glutamylcysteine_synthetase_subunits_in_the_Rat_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0041-008X(99)98729-X DB - PRIME DP - Unbound Medicine ER -