Browsing by Author "Paterson, A.C."
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Item Effects of exogenous antioxidants on dietary iron overload.(The Society for Free Radical Research, Japan, 2009) Asare, G. A.; Kew, M.C.; Mossanda, K.S.; Paterson, A.C.; Siziba, K.; Kahler-Venter, C.P.In dietary iron overload, excess hepatic iron promotes liver damage. The aim was to attenuate free radical-induced liver damage using vitamins. Four groups of 60 Wistar rats were studied: group 1 (control) was fed normal diet, group 2 (Fe) 2.5% pentacarbonyl iron (CI) followed by 0.5% Ferrocene, group 3 (Fe + V gp) CI, Ferrocene, plus vitamins A and E (42x and 10x RDA, respectively), group 4 (Fe - V gp) CI, Ferrocene diet, minus vitamins A and E. At 20 months, glutathione peroxidase (GPx), superoxide dismutase (SOD), Oxygen Radical Absorbance Capacity (ORAC), Ames mutagenicity test, AST, ALT and 4-hydroxynonenal (4-HNE) immunohistochemistry were measured. 8OHdG levels of the Fe + V and Fe - V groups were 346 +/- 117 and 455 +/- 151, ng/g w.wt, respectively. Fe + V and Fe - V differences were significant (p<0.005). A positive correlation between DNA damage and mutagenesis existed (p<0.005) within the iron-fed gps. AST levels for Fe + V and Fe - V groups were 134.6 +/- 48.6 IU and 202.2 +/- 50.5 IU, respectively. Similarly, ALT levels were 234.6 +/- 48.3 IU and 329.0 +/- 48.6 IU, respectively. However, Fe - V and Fe + V groups transaminases were statistically insignificant. 4-HNE was detected in Fe + V and Fe - V gp livers. Vitamins A and E could not prevent hepatic damage.Item Hepatocellular carcinoma caused by iron overload: A possible mechanism of direct hepatocarcinogenicity.(2006-02-16) Asare, G.A.; Mossanda, K.S.; Kew, M.C.; Paterson, A.C.; Kahler-Venter, C.P.; Siziba, K.BACKGROUND/AIMS: Excess hepatic iron may be both directly and indirectly carcinogenic. The aim of this study was to determine if generation of reactive oxygen species and the resulting oxidative damage induced by free hepatic iron is directly hepatocarcinogenic. METHODS: Sixty male Wistar albino rats were iron-loaded by ferrocene supplementation of their diet. Biochemical parameters of oxidative damage and lipid peroxidation, DNA unwinding and strand breaks, and the Ames Mutagenesis Test were measured at 4 monthly intervals and correlated with the degree of hepatic iron overload, the presence of iron-free preneoplastic foci in the liver, and the development of hepatocellular carcinoma in comparison with 60 control rats. RESULTS: Levels of lipid hydroperoxides, malonaldehyde, 8-isoprostane and 8-hydroxy-2'-deoxyguanosine increased, reaching peak concentrations at 20-24 months, and correlating with an increase in the rate of DNA unwinding, strand breaks, and positive Ames Tests. Iron-free neoplastic foci became evident at 16 months and thereafter increased in number. Preneoplastic foci were present in five of eight rats remaining at 32 months and HCC had developed in one of the five. CONCLUSIONS: Our findings are compatible with the hypothesis that the direct hepatocarcinogenic effect of free iron is mediated by the generation of oxygen reactive species and oxidative damage that are mutagenic and carcinogenic.Item Iron-free neoplastic nodules and hepatocellular carcinoma without cirrhosis in wistar rats fed a diet high in iron.(2006) Asare, G.A.; Paterson, A.C.; Kew, M.C.; Khan, S.; Mossanda, K.S.Although excess hepatic iron in hereditary haemochromatosis and dietary iron overload in the African causes hepatocellular carcinoma, it usually does so in the presence of cirrhosis. A direct hepatocarcinogenic effect of iron has not been proved. Moreover, an animal model of hepatocellular carcinoma induced by iron overload has not been available. The aim of this study was to develop such a model and to use it to ascertain whether excess hepatic iron is directly hepatocarcinogenic. Sixty Wistar albino rats were fed a chow diet and 60 the same diet supplemented initially with 2% carbonyl iron for 12 months, followed by 0.5% ferrocene for 20 months. Five rats from each group were sacrificed every 4 months for 24 months for histological and biochemical monitoring. By 16 months, hepatocytes in all the rats receiving the iron-supplemented diet showed grade 4 iron overload, comparable in degree with that seen in patients with advanced hereditary haemochromatosis and dietary iron overload. Altered hepatic foci and pre-neoplastic nodules were first seen at 16 months. These increased in size and number with time, were iron-free, stained positively with placental glutathione sulphydryl transferase, and showed the same histological features as the iron-free foci described in patients with hepatocellular carcinoma complicating hereditary haemochromatosis. At 32 months the eight surviving rats in the iron overloaded group were sacrificed. The livers of five of these rats contained pre-neoplastic nodules and one showed, in addition, an iron-free, well-differentiated hepatocellular carcinoma. The tumour stained positively for placental glutathione sulphydryl transferase. Neither cirrhosis nor portal fibrosis was present in this or any iron-loaded animal. We conclude that hepatocellular carcinoma may complicate dietary hepatic iron overload in Wistar albino rats in the absence of fibrosis or cirrhosis, confirming an aetiological association between dietary iron overload and the tumour and suggesting that iron may be directly hepatocarcinogenic.