Abstract |
Previous studies show that cytotoxic activated macrophages cause inhibition of DNA synthesis, inhibition of mitochondrial respiration, and loss of intracellular iron from tumor cells. Here we examine aconitase, a citric acid cycle enzyme with a catalytically active iron- sulfur cluster, to determine if iron- sulfur clusters are targets for activated macrophage-induced iron removal. Results show that aconitase activity declines dramatically in target cells after 4 h of co-cultivation with activated macrophages. Aconitase inhibition occurs simultaneously with arrest of DNA synthesis, another early activated macrophage-induced metabolic change in target cells. Dithionite partially prevents activated macrophage induced aconitase inhibition. Furthermore, incubation of injured target cells in medium supplemented with ferrous ion plus a reducing agent causes near-complete reconstitution of aconitase activity. The results show that removal of a labile iron atom from the [4Fe-4S] cluster, by a cytotoxic activated macrophage-mediated mechanism, is causally related to aconitase inhibition.
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Authors | J C Drapier, J B Hibbs Jr |
Journal | The Journal of clinical investigation
(J Clin Invest)
Vol. 78
Issue 3
Pg. 790-7
(Sep 1986)
ISSN: 0021-9738 [Print] United States |
PMID | 3745439
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Citrates
- Ferrous Compounds
- Iron-Sulfur Proteins
- Lipopolysaccharides
- Metalloproteins
- Dithionite
- Citric Acid
- DNA
- Iron
- Isocitrate Dehydrogenase
- Aconitate Hydratase
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Topics |
- Aconitate Hydratase
(antagonists & inhibitors, metabolism)
- Animals
- Cell Line
- Citrates
(metabolism)
- Citric Acid
- DNA
(biosynthesis)
- Dithionite
(pharmacology)
- Female
- Ferrous Compounds
(pharmacology)
- Iron
(metabolism)
- Iron-Sulfur Proteins
(metabolism)
- Isocitrate Dehydrogenase
(metabolism)
- Kinetics
- Lipopolysaccharides
(pharmacology)
- Macrophage Activation
- Macrophages
(physiology)
- Male
- Metalloproteins
(metabolism)
- Mice
- Mice, Inbred C3H
- Neoplasms, Experimental
(enzymology)
- Oxygen Consumption
- Spectrophotometry
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