Transport of glutathione by renal basal-lateral membrane vesicles

doi:10.1016/0006-291X(83)91796-5

Biochemical and Biophysical Research Communications

Volume 112, Issue 1, 15 April 1983, Pages 55-60

https://doi.org/10.1016/0006-291X(83)91796-5 Get rights and content

Abstract

Transport of glutathione was studied in membrane vesicles derived from the basal-lateral region of the plasma membrane of rat kidney proximal tubules. The integrity of the vesicle preparation was demonstrated by showing that vesicles were osmotically sensitive, with GSH uptake at equilibrium varying inversely with medium osmolality. Analysis of vesicle content by high-pressure liquid chromatography and competition experiments with glycine and cysteinylglycine confirmed that measured uptake of GSH represented transport of intact tripeptide rather than transport of degradation products. The initial rate of GSH uptake in the presence of either the sodium or potassium salt of the permeant thiocyanate anion showed that the uptake was sodium-dependent. This suggests that a GSH-Na⁺ cotransport system exists in these membranes.

References (10)

D. Häberle et al.
FEBS Lett
(1979)
M.C. Fonteles et al.
J. Surg. Res
(1976)
M.E. Anderson et al.
Biochem. Biophys. Res. Commun
(1980)
D.J. Reed et al.
Biochem. Biophys. Res. Commun
(1980)
B.B. Rankin et al.
FEBS Lett
(1982)

There are more references available in the full text version of this article.

Cited by (75)

Renal Glutathione: Dual roles as antioxidant protector and bioactivation promoter
2024, Biochemical Pharmacology
The tripeptide glutathione (GSH) possesses two key structural features, namely the nucleophilic sulfur and the γ-glutamyl isopeptide bond. The former allows GSH to serve as a critical antioxidant and anti-electrophile. The latter allows GSH to translocate throughout the systemic circulation without being degraded. The kidneys exhibit several unique processes for handling GSH. This includes the extraction of 80% of plasma GSH, in part by glomerular filtration but mostly by transport across the basolateral plasma membrane. Studies on the protective effect of exogenous GSH are summarized, showing the different inherent susceptibility of proximal tubular and distal tubular cells and the impact on pathological or disease states, including hypoxia, diabetic nephropathy, and compensatory renal growth associated with uninephrectomy. Studies on mitochondrial GSH transport show the coordination between the citric acid cycle and oxidative phosphorylation in generating driving forces for both plasma membrane and mitochondrial carriers. The strong protective effects of increasing expression and activity of these carriers against oxidants and mitochondrial toxicants are summarized. Although GSH plays a cytoprotective role in most situations, two distinct exceptions to this are presented. In contrast to expectations, overexpression of the mitochondrial 2-oxoglutarate carrier markedly increased cell death from exposure to the nephrotoxic chemotherapeutic drug cisplatin (CDDP). Another key example of GSH serving a bioactivation role in the kidneys, rather than a detoxification role, is the metabolism of halogenated alkenes such as trichloroethylene (TCE). Although considerable research has gone into this topic, unanswered questions and emerging topics remain and are discussed.
Trichloroethylene biotransformation and its role in mutagenicity, carcinogenicity and target organ toxicity
2014, Mutation Research - Reviews in Mutation Research
Citation Excerpt :
Renal plasma DCVG can be a substrate for one of three putative carriers on the basolateral plasma membrane. Work by Lash and Jones [163,164] defined the processes of basolateral GSH uptake, demonstrating energy-dependent and both Na+-coupled and Na+-independent transport. They further showed that, like many membrane transporters, these carriers have somewhat broad substrate specificities and can also transport various γ-glutamyl amino acids and GSH S-conjugates, including DCVG [165].
Metabolism is critical for the mutagenicity, carcinogenicity, and other adverse health effects of trichloroethylene (TCE). Despite the relatively small size and simple chemical structure of TCE, its metabolism is quite complex, yielding multiple intermediates and end-products. Experimental animal and human data indicate that TCE metabolism occurs through two major pathways: cytochrome P450 (CYP)-dependent oxidation and glutathione (GSH) conjugation catalyzed by GSH S-transferases (GSTs). Herein we review recent data characterizing TCE processing and flux through these pathways. We describe the catalytic enzymes, their regulation and tissue localization, as well as the evidence for transport and inter-organ processing of metabolites. We address the chemical reactivity of TCE metabolites, highlighting data on mutagenicity of these end-products. Identification in urine of key metabolites, particularly trichloroacetate (TCA), dichloroacetate (DCA), trichloroethanol and its glucuronide (TCOH and TCOG), and N-acetyl-S-(1,2-dichlorovinyl)-l-cysteine (NAcDCVC), in exposed humans and other species (mostly rats and mice) demonstrates function of the two metabolic pathways in vivo. The CYP pathway primarily yields chemically stable end-products. However, the GST pathway conjugate S-(1,2-dichlorovinyl)glutathione (DCVG) is further processed to multiple highly reactive species that are known to be mutagenic, especially in kidney where in situ metabolism occurs. TCE metabolism is highly variable across sexes, species, tissues and individuals. Genetic polymorphisms in several of the key enzymes metabolizing TCE and its intermediates contribute to variability in metabolic profiles and rates. In all, the evidence characterizing the complex metabolism of TCE can inform predictions of adverse responses including mutagenesis, carcinogenesis, and acute and chronic organ-specific toxicity.
Glutathione transporters
2013, Biochimica et Biophysica Acta - General Subjects
Citation Excerpt :
Based upon experimental evidences from many studies, two main mechanisms of glutathione uptake into the mammalian cells may be operating. Biochemical studies have shown the existence of Na+ dependent and Na+ independent glutathione transport systems in different tissues such as renal basolateral membrane [20,59], small intestine [18], and brain cells [60]. The uptake of the GSH molecule into renal proximal tubular cells occurred despite the irreversible inhibition of γ-GT by acivicin [20,59], providing strong evidence for existence of a transport system to take up intact glutathione molecule in the kidney cells.
Glutathione (GSH) is synthesized in the cytoplasm but there is a requirement for glutathione not only in the cytoplasm, but in the other organelles and the extracellular milieu. GSH is also imported into the cytoplasm. The transports of glutathione across these different membranes in different systems have been biochemically demonstrated. However the molecular identity of the transporters has been established only in a few cases.
An attempt has been made to present the current state of knowledge of glutathione transporters from different organisms as well as different organelles. These include the most well characterized transporters, the yeast high-affinity, high-specificity glutathione transporters involved in import into the cytoplasm, and the mammalian MRP proteins involved in low affinity glutathione efflux from the cytoplasm. Other glutathione transporters that have been described either with direct or indirect evidences are also discussed.
The molecular identity of a few glutathione transporters has been unambiguously established but there is a need to identify the transporters of other systems and organelles. There is a lack of direct evidence establishing transport by suggested transporters in many cases. Studies with the high affinity transporters have led to important structure-function insights.
An understanding of glutathione transporters is critical to our understanding of redox homeostasis in living cells. By presenting our current state of understanding and the gaps in our knowledge the review hopes to stimulate research in these fields. This article is part of a Special Issue entitled Cellular functions of glutathione.
Targeting maladaptive glutathione responses in lung disease
2011, Biochemical Pharmacology
The lung is unique being exposed directly to the atmospheric environment containing xenobiotics, pathogens, and other agents which are continuously inhaled on a daily basis. Additionally, the lung is exposed to higher ambient oxygen levels which can promote the formation of a complex number of reactive oxygen and nitrogen species. Due to this constant barrage of potential damaging agents, the lung has developed a high degree of plasticity in dealing with ever changing conditions. In the present commentary, we will focus on glutathione (GSH) as a key antioxidant in the lung airways and discuss mechanisms by which the lung uses GSH to adapt to its rapidly changing environment. We will then examine the evidence on how defective and inadequate adaptive responses can lead to lung injury, inflammation and disease. Lastly, we will examine some of the recent attempts to alter lung GSH levels with therapies in a number of human lung diseases and discuss some of the limitations of such approaches.
Cytoprotective Systems within the Kidney
2010, Comprehensive Toxicology, Second Edition
The kidneys are particularly susceptible to injury from a diverse array of chemicals and drugs, including some that are therapeutic agents for which nephrotoxicity limits their efficacy. Additionally, several diseases and pathological states, such as diabetes and cardiovascular disease, exhibit renal dysfunction as a significant complication. Accordingly, identification of protective agents or development of strategies to prevent cell death or enhance cellular repair and/or proliferation is needed. This chapter will review cytoprotective mechanisms in renal proximal tubular cells, focusing on three classes of processes that have been the best studied: (1) thiol-disulfide redox protectants, including the glutathione and thioredoxin systems, metallothionein, N-acetyl-l-cysteine, and other low-molecular-weight thiols; (2) modulation of signaling pathways, involving epidermal growth factor, the mitogen-activated protein kinase family, protein kinase C and B (Akt), heat shock proteins, p53 and p21, peroxisome proliferator activator receptor-γ coactivator-1α (PGC-1α), BH3-family proteins, and the Nrf2 and NF-κB pathways; and (3) modulation of renal physiological function, focusing on intracellular pH and glycine and chloride channels. While this listing of cytoprotective mechanisms that can function in the kidneys is by no means complete, it demonstrates the diversity and breadth of protective systems that serve to balance the susceptibility of the kidneys, in particular the proximal tubular cells, and restore cellular and/or tissue function in disease states or after toxic insults.
Amino Acids, Oligopeptides, and Hyperaminoacidurias
2008, Seldin and Giebisch's The Kidney

View all citing articles on Scopus

View full text

Transport of glutathione by renal basal-lateral membrane vesicles

Abstract

FEBS Lett

J. Surg. Res

Biochem. Biophys. Res. Commun

Biochem. Biophys. Res. Commun

FEBS Lett