Glutathione <i>S</i>‐conjugates stimulate ATP hydrolysis in the plasma membrane fraction of rat hepatocytes

Nicotera, Pierluigi; Baldi, C.; Svensson, Sten‐Åke; Larsson, Rolf; Bellomo, Giorgio; Orrenius, Sten

doi:10.1016/0014-5793(85)81226-6

Cited by 34 publications

(8 citation statements)

References 24 publications

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“…cells were treated under the conditions noted above (data not shown). This finding suggests that the BmCl-GSH adduct was actively excreted by the hepatocytes, possibly via the transport system previously reported to be involved in excreting GSH conjugates from hepatocytes (27). Moreover, the kinetics of BmCl-GSH fluorescence decay suggest that the conjugate was first released from the nucleus into the cytoplasm and subsequently from the cytoplasm into the extracellular space.…”

Section: Resultssupporting

confidence: 56%

Demonstration of nuclear compartmentalization of glutathione in hepatocytes.

Bellomo

Vairetti

Stivala

et al. 1992

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

209

136

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The intracellular distribution of glutathine (GSH) in cultured hepatocytes hasbeen investigated by using the compound monochlorobimane (BmCI) Approximately 10-20% of total cellular GSH in rat liver is sequestered in the mitochondrial matrix (6, 7). The size ofthis pool depends on cytosolic GSH synthesis (8) and the active transport of GSH into mitochondria via a multicomponent system recently described (9).Conventional cell-fractionation studies have not provided evidence for the existence of functionally distinct pools of GSH in hepatocytes other than those in the cytosol and mitochondria. Despite the known functions of GSH in DNA synthesis (10) and protection from oxidative DNA damage (11), little is known about the nuclear localization ofGSH and the factors regulating the nuclear GSH level. Tirmenstein and Reed (12), using fractionation and centrifugation techniques in nonaqueous medium, measured the nuclear GSH content in rat kidney and found values similar to those in the cytosol. Other fractionation techniques (such as selective permeabilization of cell constituents with various detergents) provided equivocal results (13,14). However, the latter investigations have suggested that a nuclear pool of GSH may exist in intact cells.Recent advances in image-analysis technology, together with the development of additional, nontoxic fluorescent indicators that can be used in intact cells, have facilitated an enormous input into the study of various aspects of cell physiology (15,16 ITo whom reprint requests should be addressed. 4412The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

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Section: Resultssupporting

confidence: 56%

Demonstration of nuclear compartmentalization of glutathione in hepatocytes.

Bellomo

Vairetti

Stivala

et al. 1992

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

209

136

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“…Ionizing radiation causes radiolysis of bound and solvent water in the cell, producing hydroxyl radicals, superoxide radicals, and hydrogen peroxide (16,17). Oxidants such as hydrogen peroxide and superoxide can induce activation of PLC-y, leading to Ca2+ mobilization and PKC activation (18,19). The catalytic activity of PLC-y is regulated through tyrosine phosphorylation by receptor-and non-receptor-type PTKs (4,20,21), and biochemical signals that trigger tyrosinespecific protein phosphorylation have been shown to precede the activation of PLC-y and stimulation of PtdIns turnover in many experimental systems (3,4,20,21).…”

Section: Methodsmentioning

confidence: 99%

Tyrosine phosphorylation is a mandatory proximal step in radiation-induced activation of the protein kinase C signaling pathway in human B-lymphocyte precursors.

Uckun

Schieven

Tuel‐Ahlgren

et al. 1993

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

118

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Ionizing radiation triggers a signal in human B-lymphocyte precursors that is intimately flked to an active protein-tyrosine kinase regulatory pathway. We show that in B-lympbocyte precursors, irradiation with -rays leads to (i) stimulation of phosphatidylinosltol turnover; (i) downstream activation by covalent modification of multiple swine-specific protein kinases, including protein kinase C; and (iii) activation of nuclear factor KB. All of the radiation-induced signals were effectively prevented by the protein-tyrosine kinase hiitors genistein and herbimycin A. Thus, tyrosine plosphorylation is an important and perhaps mandatory proximal step in the activation of the protein kinase C signaling cascade in human B-lymphocyte precursors. Our report expands current knowledge of the radiation-induced signaling cascade by clarifying the chronological sequence of biochemical events that follow irradiation.Weichselbaum and colleagues (1, 2) have proposed that irradiation initiates a cascade of cytoplasmic signaling events in mammalian cells. In particular, ionizing radiation stimulates the transcription of immediate early response genes that encode transcriptional factors, by activation of a protein kinase C (PKC)-dependent cytoplasmic signaling pathway (1, 2). However, radiation-induced signaling events proximal to PKC activation require further evaluation.Protein-tyrosine kinases (PTKs) are key participants in the initiation of signal cascades that affect proliferation and survival of human B-lymphocyte precursors (3, 4). We have recently shown that ionizing radiation stimulates several PTlKs in human B-lymphocyte precursors, including the Src family tyrosine kinases p59fyn and p55bIk, leading to enhanced tyrosine phosphorylation of multiple substrates and triggering apoptosis (5). Since PTKs play myriad roles in the regulation of cell function and proliferation (6, 7), the activation of a PIK cascade and tyrosine phosphorylation may explain the pleiotropic effects of ionizing radiation on cellular functions.The present study expands earlier work by specifically examining the role of tyrosine phosphorylation in radiationinduced activation of the PKC pathway in human B-lymphocyte precursors at discrete developmental stages of B-cell ontogeny. Notably, the tyrosine kinase inhibitors herbimycin and genistein effectively inhibited radiation-induced activation of PKC (PK76) and PKC-dependent seine kinases PK55 and PK50. Furthermore, the activation of nuclear factor KB (NF-KB) in irradiated B-lymphocyte precursors was abrogated by pretreatment with herbimycin or genistein. Our results indicate that radiation-induced activation of the PKC signaling cascade leads to downstream activation of multiple serine-specific protein kinases, and activation of NF-KB. The evidence provided reveals that these events are triggered by radiation-induced stimulation of tyrosine-specific protein kinases. MATERIALS AND METHODSPatient Material and Cell Lines. We used the CD19+CD10+ CasIgM-pre-pre-B cell line REH, the CD19+CD10+ CsIgM...

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“…A common translocator driven by ATP hydrolysis has been postulated as the molecular identity involved in the transport of different glutathione-Sconjugates. The existence of this translocator has been experimentally supported by Nicotera et al (1985), and subsequently by others (Oude Elferink et al, 1991). A typical feature of this transporter is its preferential topological location in the bile canalicular domain of the hepatocyte plasma membrane (Oude Elferink et al, 1993).…”

Section: Formation Distribution and Efflux Of The Monochlorobimane-gmentioning

confidence: 80%

Intranuclear distribution, function and fate of glutathione and glutathione-S-conjugate in living rat hepatocytes studied by fluorescence microscopy

Bellomo

Palladini

Vairetti

1997

Microsc. Res. Tech.

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Glutathione S‐conjugates stimulate ATP hydrolysis in the plasma membrane fraction of rat hepatocytes

Cited by 34 publications

References 24 publications

Demonstration of nuclear compartmentalization of glutathione in hepatocytes.

Demonstration of nuclear compartmentalization of glutathione in hepatocytes.

Tyrosine phosphorylation is a mandatory proximal step in radiation-induced activation of the protein kinase C signaling pathway in human B-lymphocyte precursors.

Intranuclear distribution, function and fate of glutathione and glutathione-S-conjugate in living rat hepatocytes studied by fluorescence microscopy

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