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Thesis (Ph. D.)--University of Adelaide, 1987. / Includes bibliographical references (leaves 181-201).

Thesis (Ph. D.)--University of Wisconsin--Madison, 1983. / Typescript. Vita. Description based on print version record. Includes bibliographical references (leaves 112-144).

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Bibliography: leaves 181-201.

Vitamin A and its chemical analogues (retinoids) are known to play a role in the maintenance and differentiation of epithelial tissue. Retinoids have been shown to inhibit carcinogenesis in a number of tissues in experimental animals and to inhibit the growth of various untransformed and cancer cell lines in vitro. This study investigated the effect of retinyl acetate supplemented at concentrations of 1 μM, 5 μM, 10 μM and 100 μM to in vitro cultured untransformed LLCMK cells, and transformed BL-6 melanoma and human hepatoma cell lines. A small but non-significant effect of vitamin A addition on the growth of the untransformed cells was observed, while substantial inhibition of proliferation of the two tumour cell lines was found. At the cytotoxic level of 100 μM supplemented vitamin A, all three cell lines showed marked inhibition of growth. This led to an electron microscopy study to examine the ultrastructural effect of the vitamin A addition. At the low non-toxic levels of vitamin A addition (1 - 10 μM), no ultrastructural changes were observed in the untransformed cells. However, at a level of 5 μM and 10 μM vitamin A addition in the tumour cells, an increase in the size of suspected lipid droplets was observed. At the cytotoxic level of 100 μM supplemented vitamin A, large lipid droplets were very apparent, as was much cellular degeneration. This effect was more marked in the tumour cells than in the untransformed cells. The lipid nature of the droplets was confirmed by using the lipid stain, Sudan IV. In order to investigate the effect of added vitamin A at the cell surface level, an ELISA system was used to quantify the level of the cell surface glycoprotein, fibronectin, in the culture media. Vitamin A plays an important role in the production of mature fibronectin by participating in the glycosylation of the molecule. This study showed no major effect of added vitamin A on the release of fibronectin into the culture media. This did not, however, exclude the possibility that the vitamin A was involved in the production and enhanced binding of fibronectin to the cell surface, and was possibly also exerting an effect on the availability of fibronectin receptors. Further studies would, however, be required to substantiate such effects of vitamin A supplementation. No single mechanism of action of vitamin A on tumour cell growth inhibition was identified, but the possibility that at least two mechanisms exist, was suggested

Call number: LD2668 .T4 1931 G51

The most important and novel finding of this work was enhanced liver Kupffer cell phagocytic and metabolic function by hypervitaminosis A. An animal model of hypervitaminosis A was developed in male Sprague-Dawley rats gavaged with 250,000 I.U. retinol/Kg body weight/day for 3 weeks. Presence of hypervitaminosis A was indicated by characteristic changes in the fur coat, presence of brittle bones and spontaneous fractures and a significant increase in plasma and liver concentrations of retinyl palmitate while retinol levels remained the same as in controls. Hypervitaminosis A did not cause severe liver abnormalities as reflected by normal plasma glutamate pyruvate transaminase activity and bilirubin. Hepatic blood flow and portal pressure were also normal. Liver microsomal cytochrome P-450 was decreased while malondialdehyde, a by-product of lipid peroxidation, was increased by the Vitamin A treatment. Examination of liver tissue by light microscopy showed no signs of liver cell injury. The main change was a marked increase in size of the fat or Vitamin A storing cells. Although hypervitaminosis A itself did not cause severe liver damage, pretreatment with high doses of Vitamin A severely potentiated liver injury by known hepatotoxicants such as carbon tetrachloride, endotoxin and acetaminophen. The potentiation of hepatotoxicity was determined by activity of glutamate pyruvate transaminase in plasma as well as by histological examination of liver tissue. Measurement of clearance from blood of indocyanine green and ⁹⁹ᵐTc-disofenin indicated this hepatocyte function was normal. Kupffer cell phagocytic function was enhanced in hypervitaminosis A as determined by clearance from blood of ⁹⁹ᵐTc-sulfur colloid. In vitro, there was also evidence that treatment with high doses of Vitamin A activated or enhanced Kupffer cell function. Kupffer cells from control and Vitamin A treated rats were isolated by enzymatic dispersion, purified by centrifugal elutriation, and placed in culture. Activation was indicated by (1) increased phagocytosis of ⁵¹Cr-labeled opsonized sheep red blood cells (2) enhanced release of superoxide anion and (3) enhanced production of tumor cytolytic factor by Kupffer cells from Vitamin A treated rats. Stimulation of Kupffer cell function in hypervitaminosis A seemed to be via lymphokines produced by lymphocytes in response to the excess Vitamin A. We propose that activated Kupffer cells may play an important role in liver injury in hypervitaminosis A.

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No description available.