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Toxicology of trace metals : metallothionein production and carcinogenesis Brown, David Arthur

Abstract

Many reports of trace metal levels in organisms from polluted areas exist in the literature, but little can be inferred from these data as to the actual biological significance of these metal levels to the exposed organism. This study reports a biochemically meaningful assay based upon the actual toxicology of the trace metals: it measures the levels of those metals that are bound by the trace metal detoxifying protein, metallothionein, and those which are free to exert toxic effects by binding enzymes in the high molecular weight protein pool. Further, a study was made of trace metal changes in carcinogenesis in order to elucidate the role of trace metals in the etiology of cancer. Organisms were sampled from an area known to be polluted with trace metals. Tissues were homogenized, centrifuged, and the supernatants fractionated according to molecular weight by passing through a. column packed with Pharmacia G-75 gel. Copper and zinc were present in the high molecular weight protein pool in relatively high levels, as they are components of metal loenzymes. Excesses of Cu and Zn were stored on metallothionein. In duck liver and kidney tissue, cadmium was bound to metallothionein unless the high molecular weight protein pool was Zn deficient. In this case, high levels of Cd appeared in the high molecular weight protein pool, presumably since Cd was then more effectively able to compete with Zn for Zn-binding sites in metalloenzymes. Mussels were exposed to Cd, Cu and Zn near a sewer out- fall and in the laboratory. Reduced survival did not occur until metallothionein was apparently metal saturated, and there was a rapid increase of metals in the high molecular weight protein pool. Phytoplankton, zooplankton and fish were exposed to mercury. Growth rates were reduced in those exposures where Hg was detectable in the high molecular weight protein pool. In fish and zooplankton, this occurred when the capacity of metallothionein to bind Hg was apparently surpassed. Copper and zinc levels decreased in the high molecular weight protein pool with increasing Hg exposure level. Toxic effects of trace metals are attributed to the interference of nonessential metals with essential metals in metalloenzymes. Both cancerous fish and humans had increases of Cd and the Cd:Zn ratio in the high molecular weight protein pool. In control organisms, a much higher portion of Cd.was bound to metallothionein. When mice were exposed to low Cd doses, most Cd accumulated on metallothionein. When the carcinogen diethylnitrosamine (DEN) was administered with this Cd, more Cd accumulated in the high molecular weight protein pool. Since Zn was decreased in the high molecular weight protein pool by DEN exposure, it is reasonable to conclude that, as in ducks with Zn deficient high molecular weight protein pools, Cd was more effectively able to compete for metalloenzyme binding sites. It is suggested that Cd, in cancerous organisms, might be interfering with the Zn-containing enzymes involved in cell division processes. Exposure to DEN alone resulted in decreases of Cd, Cu and Zn in the high and low molecular weight pools, and on metallothionein. Concurrent administration of Zn with DEN reversed losses of Cu and Zn slightly, and increased survival time. When low levels of Cd were administered with DEN, losses of Cu and Zn were increased, and pretumorous histological changes were more evident. Very high Cd doses increased levels of Cu and Zn in the high molecular weight protein pool over control values, and greatly increased time to death due to tumors.

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