Murine cytotoxic activated macrophages inhibit aconitase in tumor cells. Inhibition involves the iron-sulfur prosthetic group and is reversible.

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.
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.)
Chemical References	Citrates Ferrous Compounds Iron-Sulfur Proteins Lipopolysaccharides Metalloproteins Dithionite Citric Acid DNA Iron Isocitrate Dehydrogenase Aconitate Hydratase
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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