Intracellular iron status as a hallmark of mammalian cell susceptibility to oxidative stress: a study of L5178Y mouse lymphoma cell lines differentially sensitive to H2O2

Lipiński, Paweł; Drapier, Jean‐Claude; Oliveira, Leonor; Retmańska, Hanna; Sochanowicz, Barbara; Kruszewski, Marcin

doi:10.1182/blood.v95.9.2960.009k13_2960_2966

Cited by 69 publications

(36 citation statements)

References 44 publications

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“…28 The amount of IRE binding activity displayed by IRP1 or IRP2 is believed to be inversely related to the size of the labile iron pool in cells. 29,30 Liver IRP1 (Fig. 2C) and IRP2-RNA-binding capacities (data not shown) showed similar responses to increasing doses of iron dextran: there was a decrease of about 50% in mice receiving the lowest dose of iron (50 mg/kg body weight) and minimal levels were reached at 150 mg iron/kg.…”

Section: Role Of Iron In Ala-treated Pcb126-pretreated Cyp1a2(؉/؉) Micementioning

confidence: 74%

“…The decreases in RNA-binding IRP1 (which paralleled decreases in protoporphyrin) are thought to reflect increases in freely available iron. [28][29][30] Protoporphyrin accumulation is attributed to the high flux through the heme biosynthetic pathway from excess ALA making the ferrochelatase step (i.e., the insertion of ferrous iron into protoporphyrin), a rate-limiting step in heme synthesis (Fig. 1).…”

Section: Discussionmentioning

confidence: 99%

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Uroporphyria in mice: Thresholds for hepatic CYP1A2 and iron

Gorman¹,

Ross²,

Walton³

et al. 2002

Hepatology

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In mice treated with 5-aminolevulinic acid (ALA) and polyhalogenated aromatic compounds, the levels of both hepatic cytochrome P450 (CYP)1A2 and iron-which can be quite different among inbred strains-are critical in causing experimental uroporphyria. Here we investigate the development of uroporphyria as a function of CYP1A2 and iron levels in the liver of mice having a common C57BL/6 genetic background. We compared Cyp1a2(؊/؊) knockout mice, Cyp1a2(؉/؊) heterozygotes, Cyp1a2(؉/؉) wild type, and Cyp1a2(؉/؉) mice pretreated with a low dose of 3,3 ,4,4 ,5-pentachlorobiphenyl (PCB126) (4 g/kg). Cyp1a2(؉/؊) mice contain about 60% of the hepatic CYP1A2 content of Cyp1a2(؉/؉) mice, and the PCB126-pretreated Cyp1a2(؉/؉) mice have about twice the wild-type levels of CYP1A2. ALA-and iron-treated Cyp1a2(؉/؉) mice are known to accumulate hepatic uroporphyrin; this accumulation was increased 7-fold by pretreatment with the low dose of PCB126. ALA-and iron-treated Cyp1a2(؉/؊) heterozygote mice accumulated no uroporphyrin in 4 weeks, but by 8 weeks accumulated significant amounts of uroporphyrin. As previously reported, the ALA-and iron-treated Cyp1a2(؊/؊) knockout mouse has no CYP1A2 and exhibits no detectable uroporphyrin accumulation. Iron dose-response curves in ALA-and PCB126-treated Cyp1a2(؉/؉) mice showed that hepatic iron levels greater than 850 g/g liver were required to produce significant uroporphyrin accumulation in the liver. Other measures of hepatic effects of iron (iron-response element-binding protein [IRP]-iron response element [IRE]binding activity and accumulation of protoporphyrin from ALA) decreased when the level of iron was considerably lower than 850 g/g liver. At low iron doses, accumulation of iron was principally in Kupffer cells, whereas at the higher doses (required to stimulate uroporphyrin accumulation), more iron was found in parenchymal cells. We conclude that small changes in hepatic CYP1A2 levels can dramatically affect uroporphyria in C57BL/6 mice, providing the animals have been sufficiently loaded with iron; these data might be clinically relevant to acquired (sporadic) porphyria cutanea tarda, because humans show greater than 60-fold genetic differences in hepatic basal CYP1A2. (HEPATOLOGY 2002;35:912-921.)

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Section: Role Of Iron In Ala-treated Pcb126-pretreated Cyp1a2(؉/؉) Micementioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Uroporphyria in mice: Thresholds for hepatic CYP1A2 and iron

Gorman¹,

Ross²,

Walton³

et al. 2002

Hepatology

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“…Oxidative stress also significantly stimulated ferritin synthesis (65). Intracellular labile iron concentrations are considered by some researchers to reflect the cell's susceptibility to oxidative stress (70). There is no doubt, however, that the cytosolic iron pool does regulate iron uptake, principally through changes in IRP2.…”

Section: Whilementioning

confidence: 99%

Molecular regulation of iron homeostasis and resistance to infection in alcoholics

Barry¹

2002

Front Biosci

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Chronic alcohol abuse is associated with both an altered response to infection and deranged iron homeostasis. While both clinical manifestations are well known, the inter-relationships between alcohol and iron and the response to infection are not. The recent identification of a plethora of iron regulatory and transport proteins has now begun to explain these relationships. This article outlines the current state of knowledge on cellular iron homeostasis, with particular reference to the iron regulatory proteins (IRP1, IRP2 and HFE) and the iron membrane transport proteins, two of which have been shown to be members of the natural resistance- associated macrophage protein family (Nramp1 and 2). Following this introduction, the response of the body to infection, in terms of iron withholding is discussed at the cellular level, especially in terms of the macrophage and its cytokine-mediated responses. Prior alterations to body iron status are also considered in this section. The effect of alcohol alone on the body's response to infection is then outlined, principally in terms of the macrophage function and cytokine regulation. These are then combined to correlate the clinical and experimental observations with known derangements produced by the individual insults of alcohol and altered iron homeostasis. on the response to infection. Particular attention is paid not only to cytokine/chemokine actions, but also to the consequences of the altered production of reactive oxygen and nitrogen species. Finally, the possible mechanisms by which alcohol and altered iron homeostasis lead to tissue damage during infection.

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“…Iron was estimated in the nuclei of LY cells by atomic absorption spectrometry and the labile iron pool (available to chelators) with calcein (Lipiñski et al, 2000). As shown in Table 2, the expectation concerning the iron content in LY sublines was justified.…”

Section: Difference In Iron Content In Ly Sublinesmentioning

confidence: 99%

“…As summarised in Table 2, the expression level of these proteins in LY sublines differs and this gives an explanation of the differential iron content. Further details on iron content control in LY sublines can be found in Lipiñski et al (2000). Vol.…”

Section: Difference In Iron Content In Ly Sublinesmentioning

confidence: 99%

The response of L5178Y lymphoma sublines to oxidative stress: antioxidant defence, iron content and nuclear translocation of the p65 subunit of NF-kappaB.

Boużyk

Grądzka²,

Iwaneńko³

et al. 2000

Acta Biochim Pol

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We examined the response to hydrogen peroxide of two L5178Y (LY) sublines which are inversely cross-sensitive to hydrogen peroxide and X-rays: LY-R cells are radioresistant and hydrogen peroxide-sensitive, whereas LY-S cells are radiosensitive and hydrogen peroxide-resistant. Higher initial DNA breaks and higher iron content (potentially active in the Fenton reaction) were found in the hydrogen peroxide sensitive LY-R cells than in the hydrogen peroxide resistant LY-S cells, whereas the antioxidant defence of LY-R cells was weaker. In particular, catalase activity is twofold higher in LY-S than in LY-R cells. The content of monobromobimane-reactive thiols is 54% higher in LY-S than in LY-R cells. In contrast, the activity of glutathione peroxidase (GPx) is about two times higher in LY-R than in LY-S cells; however, upon induction with selenium the activity increases 15.6-fold in LY-R cells and 50.3-fold in LY-S cells.Altogether, the sensitivity difference is related to the iron content, the amount of the initial DNA damage, as well as to the efficiency of the antioxidant defence system. oxygen species, SOD, superoxide dismutase. ferential nuclear translocation of p65-NF-kB in LY sublines is due to the more efficient antioxidant defence in LY-S than in LY-R cells.Short arrows indicate the modified stages of activation (see text for explanations).

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Intracellular iron status as a hallmark of mammalian cell susceptibility to oxidative stress: a study of L5178Y mouse lymphoma cell lines differentially sensitive to H2O2

Cited by 69 publications

References 44 publications

Uroporphyria in mice: Thresholds for hepatic CYP1A2 and iron

Uroporphyria in mice: Thresholds for hepatic CYP1A2 and iron

Molecular regulation of iron homeostasis and resistance to infection in alcoholics

The response of L5178Y lymphoma sublines to oxidative stress: antioxidant defence, iron content and nuclear translocation of the p65 subunit of NF-kappaB.

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