Diminished amounts of manganese-containing superoxide dismutase have been found in all the tumors examined to date. Lowered amounts of the copper-zinc-containing superoxide dismutase have been found in many, but not all, tumors. At the same time, tumors have been shown to produce superoxide radicals. It is shown how diminished enzyme activities along with radical production may lead to many of the observed properties of cancer cells. The apparent exploitation of the differences between normal and cancer cell superoxide dismutase activity in the treatment of cancer is discussed.

/pdf/role-of-superoxide-dismutase-in-cancer-a-review-5c4fusvkkr.pdf

Role of Superoxide dismutase in cancer: a review.

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.1840110122

The pathology of hepatic iron overload: a free radical--mediated process?

Peroxidative decomposition of cellular membrane lipids is a postulated mechanism of hepatocellular injury in parenchymal iron overload. In the present study, we looked for direct evidence of lipid peroxidation in vivo (as measured by lipid-conjugated diene formation in hepatic organelle membranes) from rats with experimental chronic iron overload. Both parenteral ferric nitrilotriacetate (FeNTA) administration and dietary supplementation with carbonyl iron were used to produce chronic iron overload. Biochemical and histologic evaluation of liver tissue confirmed moderate increases in hepatic storage iron. FeNTA administration produced excessive iron deposition throughout the hepatic lobule in both hepatocytes and Kupffer cells, whereas dietary carbonyl iron supplementation produced greater hepatic iron overload in a periportal distribution with iron deposition predominantly in hepatocytes. Evidence for mitochondrial lipid peroxidation in vivo was demonstrated at all three mean hepatic iron concentrations studied (1,197, 3,231, and 4,216 micrograms Fe/g) in both models of experimental chronic iron overload. In contrast, increased conjugated diene formation was detected in microsomal lipids only at the higher liver iron concentration (4,161 micrograms Fe/g) achieved by dietary carbonyl iron supplementation. When iron as either FeNTA or ferritin was added in vitro to normal liver homogenates before lipid extraction, no conjugated diene formation was observed. We conclude that the presence of conjugated dienes in the subcellular fractions of rat liver provide direct evidence of iron-induced hepatic mitochondrial and microsomal lipid peroxidation in vivo in two models of experimental chronic iron overload.

/pdf/hepatic-lipid-peroxidation-in-vivo-in-rats-with-chronic-iron-1knw30ngdh.pdf

Hepatic lipid peroxidation in vivo in rats with chronic iron overload.

Molecular bases of cellular iron toxicity.

Iron, hemochromatosis, and hepatocellular carcinoma

Summary. The organelle pathology of liver biopsy specimens from patients with either primary or secondary haemochromatosis was investigated by analytical subcellular fractionation in combination with enzymic microanalysis. The most striking changes were found in the lysosomes. Increased total activities but decreased latent activities of enzymes selectively localized to the high density population of lysosomes was demonstrated in the iron overloaded biopsies. Depletion of the iron, where possible, by venesection was accompained by a return to normal of these changes.



The other subcellular organelles, plasma membrane, endoplasmic reticulum, biliary canaliculi, mitochondria, peroxisomes and the low density population of lysosomes appear to be relatively unaffected. The minor changes demonstrated are similar to those seen in other forms of chronic liver disease. It is suggested that iron mediated lysosomal disruption is implicated in the pathogenesis of the tissue damage in haemochromatosis.

Organelle pathology in primary and secondary haemochromatosis with special reference to lysosomal changes.

1. Highly sensitive technique are described for the assay of plasma membrane (5'-nucleotidase, alkaline phosphatase), microsomal (neutral alpha-glucosidase, leucyl-2-naphthylamidase) and biliary canalicular (gamma-glutamyltransferase) enzymes and for nine acid hydrolases (acid phosphatase, phosphodiesterase, beta-glucosidase, alpha-glucosidase, alpha-galactosidase, beta-galactosidase, alpha-mannosidase, N-acetyl-beta-glucosaminidase, beta-glucuronidase) in human liver. 2. Optimum and specific assay systems have been developed which give linear kinetics for all enzymes. 3. The range of enzyme activities in samples of human liver, obtained by closed needle biopsy, and sera have been determined.

Enzyme activities in human liver biopsies: assay methods and activities of some lysosomal and membrane-bound enzymes in control tissue and serum.

1. Iron, acid phosphatase and N -acetyl-β-glucosaminidase were assayed in liver biopsies from control subjects and patients with primary and secondary haemochromatosis. 2. The activities of the lysosomal enzymes were significantly higher in liver biopsies from patients with iron overload than in those from other patient groups. 3. Lysosomes from the livers of patients with iron overload were strikingly more fragile than those of control subjects as demonstrated by assays of latent and sedimentable N -acetyl-β-glucosaminidase. 4. Lysosomal integrity was essentially normal in biopsies from patients with a wide variety of chronic liver diseases. 5. It is suggested that iron accumulation damages the lysosomal membrane, releasing acid hydrolases into the cytoplasm and thus initiating cell damage.

Acid Hydrolase Activities and Lysosomal Integrity in Liver Biopsies from Patients with Iron Overload

1. Liver biopsy specimens obtained from patients with alcoholic liver disease of varying severity were assayed for lysosomal and microsomal enzyme activities, the results being compared with values previously obtained in control subjects. 2. Analytical subcellular fractionation by sucrose-density-gradient centrifugation was performed on extracts of the biopsies and the properties of the lysosomes, plasma membrane, biliary canaliculi and endoplasmic reticulum membranes were determined. Increased activities of plasma membrane marker enzymes, particularly γ-glutamyl transpeptidase believed to be localized to the biliary canalicular membrane, were demonstrated. These findings were most marked in alcoholic cirrhosis. The centrifugation studies revealed no abnormalities in the properties of these membranes. 3. Although the total activities of the endoplasmic reticulum marker enzyme neutral α-glucosidase were unaltered in alcoholic liver disease, centrifugation studies showed a decrease in the density distribution of the membrane-bound enzyme in cirrhosis indicating an increase in the proportion of smooth endoplasmic reticulum membranes. 4. Apart from a small decrease in activity of certain acid hydrolases in fatty liver and in cirrhosis the activities of the lysosomal enzymes were unaffected by alcoholic liver disease. 5. Measurements of lysosomal integrity and density-gradient-centrifugation studies revealed no significant abnormalities in the various patient groups apart from increased stability and reduced equilibrium density of certain lysosomes in fatty liver. It is concluded that lysosomal disruption is not implicated in the pathogenesis of alcoholic liver disease.

T. J. Peters

Papers

Organelle pathology in primary and secondary haemochromatosis with special reference to lysosomal changes.

Enzyme activities in human liver biopsies: assay methods and activities of some lysosomal and membrane-bound enzymes in control tissue and serum.

Acid Hydrolase Activities and Lysosomal Integrity in Liver Biopsies from Patients with Iron Overload

Changes in hepatic enzymes and organelles in alcoholic liver disease.

Analytical Subcellular Fractionation Studies on Human Liver Biopsies