Glutathione synthesis inhibitor butathione sulfoximine regulates ceruloplasmin by dual but opposite mechanism

Implication in hepatic iron overload

Nisha Tapryal, Chaitali Mukhopadhyay, Manoj Kumar Mishra, Dola Das, Sudipta Biswas, Chinmay K. Mukhopadhyay

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Glutathione (GSH) depletion is often detected in chronic pathological conditions like hepatitis C infection, alcohol consumption or xenobiotic assault with simultaneous reactive oxygen species (ROS) generation and hepatic iron overload. However, relation between GSH depletion and regulators of iron homeostasis is not clear so far. To determine that hepatic HepG2 cells were treated with GSH synthesis inhibitor butathione sulfoximine (BSO) and a dual regulation of ceruloplasmin (Cp) that involves in hepatic iron release was detected unlike other iron homeostasis regulators. BSO treatment that caused marginal GSH deficiency increased Cp synthesis due to increased transcription mediated by activator protein (AP)-1-binding site. In higher GSH deficiency (> 40 %) with increased ROS generation, Cp expression was decreased due to promotion of Cp mRNA decay mediated by 3'untranslated region (3'UTR) as found by transfecting chimera of chloramphenicol acetyl transferase (CAT) gene with Cp 3'UTR. RNA gel shift assay showed significant reduction in 3'UTR binding protein complex in similar condition. Decreased CAT expression and RNA-protein complex binding are reversed by pretreatment with antioxidant N-acetyl cysteine suggesting 3'UTR binding protein complex is redox-sensitive. This unique and opposite regulation of Cp provides a mechanism of hepatic iron-deposition during glutathione deficiency detected in chronic pathological conditions.

Original languageEnglish (US)
Pages (from-to)1492-1500
Number of pages9
JournalFree Radical Biology and Medicine
Volume48
Issue number11
DOIs
StatePublished - Jun 2010
Externally publishedYes

Fingerprint

Ceruloplasmin
Iron Overload
Glutathione
3' Untranslated Regions
Iron
Liver
Chloramphenicol
Transferases
Reactive Oxygen Species
Carrier Proteins
Homeostasis
Acetylcysteine
RNA-Binding Proteins
RNA
Transcription Factor AP-1
RNA Stability
Hep G2 Cells
Xenobiotics
Hepatitis C
Protein Binding

Keywords

  • AP-1
  • Ceruloplasmin
  • Gene regulation
  • Glutathione depletion
  • Hepatic iron overload
  • MRNA decay

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

Glutathione synthesis inhibitor butathione sulfoximine regulates ceruloplasmin by dual but opposite mechanism : Implication in hepatic iron overload. / Tapryal, Nisha; Mukhopadhyay, Chaitali; Mishra, Manoj Kumar; Das, Dola; Biswas, Sudipta; Mukhopadhyay, Chinmay K.

In: Free Radical Biology and Medicine, Vol. 48, No. 11, 06.2010, p. 1492-1500.

Research output: Contribution to journalArticle

Tapryal, Nisha ; Mukhopadhyay, Chaitali ; Mishra, Manoj Kumar ; Das, Dola ; Biswas, Sudipta ; Mukhopadhyay, Chinmay K. / Glutathione synthesis inhibitor butathione sulfoximine regulates ceruloplasmin by dual but opposite mechanism : Implication in hepatic iron overload. In: Free Radical Biology and Medicine. 2010 ; Vol. 48, No. 11. pp. 1492-1500.
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