Hypozincemia was induced in rats by Salmonella typhimurium and live vaccine strain Francisella tularensis (LVS) infections. Hepatic synthesis of zinc-binding proteins (ZBP) was studied in order to elucidate the mechanisms involved in the redistribution of zinc from plasma to liver occurring during infectious illness. ZBP, labeled in vivo with 65Zn, were isolated and identified as metallothioneins based, in part, on their heat stability, dimorphism, and amino acid composition. Cysteine was the major amino acid found in both forms of metallothionein and constituted 28-31% of total residues. The apparent half-life of these proteins as measured by disappearance of 65Zn was determined to be 19 h in a relatively mild infection (LVS) and 38 h in a more severe S. typhimurium infection. Results provide evidence that metallothioneins not only have the previously postulated regulatory role in normal zinc homeostasis but are intimately involved in the zinc redistribution occurring during the acute stage of infectious illness.

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Numerous chemically distinct phlogistic substances have been shown to induce hepatic metallothionein-Zn (MT) accumulation when administered to rats. These findings suggest that induction of this cysteine-rich metalloprotein occurs through the action of some common mediator(s). Possible mediators include substances such as leukocytic endogenous mediator (LEM) and/or hormones known to influence hepatic protein synthesis. Studies were performed to examine further the mechanism(s) and potential mediators involved in endotoxin-induced MT accumulation. Additionally, the studies were performed to determine the possible involvement of genetic factors, which reportedly influence LEM production, in the induced MT response. Endotoxin (ET) was administered ip to rats and to EP-resistant, C3H/HeJ, and susceptible, C3Heb/FeJ, stains of mice. ET induced hypozincemia, hyperglucagonemia, and increased MT concentrations in rats. ET induced hypozincemia and MT accumulation to the same extent in both strains of mice. The induction of tolerance in rats to Zn depressing activity of ET also prevented hyperglucagonemia and additional accumulation of MT. Results suggest that glucagon, but not LEM, may be a common mediator in MT response during inflammatory stress.

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Intraperitoneal administration of zinc (ZnIP) as zinc chloride prior to or simultaneously with a lethal quantity of intraperitoneally administered Salmonella typhimurium endotoxin significantly protected rats against toxin-induced mortality and hepatocellular damage. Pretreatment with amounts of zinc chloride ranging from 0.4 to 2.0 mg/100 g of body weight resulted in 80 to 100% survival compared with 10% survival in untreated control rats at 24 h after endotoxin treatment. Zinc chloride treatment in excess of 2.0 mg/100 g of body weight appeared to be toxic and provided diminished protection. In contrast with the protection obtained with ZnIP, intravenously administered zinc did not provide protection. The effectiveness of ZnIP to enhance survival if it was given after endotoxin was greatly diminished as a function of time after endotoxin. The extent of hepatocellular damage was assessed at various times after endotoxin administration in ZnIP-treated and untreated rats by measurement of plasma ornithine carbamoyltransferase activity and histological examination of liver sections. Endotoxin absorption from the peritoneal cavity and hepatic uptake were studied by using 51Cr-labeled endotoxin. ZnIP pretreatment significantly reduced 51Cr-labeled endotoxin content of blood and liver when compared to untreated controls, and effectively prevented endotoxin-induced elevations in plasma ornithine carbamoyltransferase activity and hepatic tissue necrosis. These data indicate that protection afforded by ZnIP treatment results as a consequence of the ability of zinc to diminish absorption of the toxin from the peritoneal cavity and subsequent hepatic uptake.