The role of dietary silver in the production of liver necrosis in vitamin E-deficient rats

Abstract

Addition of silver acetate to the diet (130–1000 ppm) or drinking water (1500 ppm) of weanling rats fed a vitamin E-deficient diet precipitates a rapidly fatal liver necrosis on Day 14 or subsequently. In the prenecrotic stage (11–13 days), the hepatocellular changes were characterized by nuclear vacuolation, by an increase in the number and size of lysosomes and by their movement away from the peribiliary area. The mitochondria were enlarged and their shape varied considerably. Some mitochondria contained rough granular material, while in others the number of electron-dense granules was reduced. Hepatocellular necrosis appearing initially in the centrilobular area rapidly involved the whole lobule. Degeneration of nuclei, mitochondria, and endoplasmic reticulum seemed to occur simultaneously. After an interval, macrophages infiltrated the necrotic area. Numerous large lysosomes containing electron-dense material (probably containing silver) could be demonstrated in these cells. No changes were observed in livers of rats given silver acetate and vitamin-E supplements. The mitochondrial changes possessed some of the features seen in rats fed a torula-yeast diet deficient in vitamin E and selenium, suggesting some degree of dysfunction. The lysosomal changes may be a consequence of such possible dysfunction. To account for the interrelationships between vitamin E, selenium, and silver seen in these and other experiments, a mechanism is put forward whereby, in the absence of vitamin E, silver reduces the availability of selenium as “selenide” in nonheme iron proteins. The result would be an impaired ability of these proteins to function as electron carriers. The widespread distribution of these proteins in nucleus, mitochondria, and endoplasmic reticulum could account for the contemporaneous lysis seen in these organelles.