Glutathione (GSH) plays several important roles in the protection of cells against oxidative damage, particularly following exposure to xenobiotics. Ferric nitrilotriacetate (Fe-NTA) is a potent depletor of GSH and also enhances tissue lipid peroxidation. In this study, we show the effect of Fe-NTA treatment on hepatic GSH and some of the glutathione metabolizing enzymes, oxidant generation and liver damage. The level of hepatic GSH and the activities of glutathione reductase, glutathione S-transferase, glutathione peroxidase, and glucose 6-phosphate dehydrogenase all decrease following Fe-NTA administration. In these parameters the maximum decrease occurred at 12 h following Fe-NTA treatment. In contrast, γ-glutamyl transpeptidase was increased at this time. Not surprisingly, the increase in the activity of γ-glutamyl transpeptidase and decreases in GSH, glutathione peroxidase, glutathione reductase, glucose 6-phosphate dehydrogenase and glutathione S-transferase were found to be dependent on the dose of Fe-NTA administered. Fe-NTA administration also enhances the production of H2O2 and increases hepatic lipid peroxidation. Parallel to these changes, Fe-NTA enhances liver damage as evidenced by increases in serum transaminases. Once again, the liver damage is dependent on the dose of Fe-NTA and is maximal at 12 h. Pretreatment of animals with antioxidant, butylated hydroxy anisole (BHA), protects against Fe-NTA-mediated hepatotoxicity further supporting the involvement of oxidative stress in Fe-NTA-mediated hepatic damage. In aggregate, our results indicate that Fe-NTA administration eventuates in decreased hepatic GSH, a fall in the activities of glutathione metabolizing enzymes and excessive production of oxidants, all of which are involved in the cascade of events leading to iron-mediated hepatic injury.

Two methods of inducing liver cirrhosis in the rat were studied. Intragastric administration of CCl₄ for 16 weeks according to Proctor and Chatamra was compared to the administration of thioacetamide in the drinking water (0.3 g/l) for the same period. CCl₄ administration induced micronodular cirrhosis in 6/8 animals with a 27% mortality. Thioacetamide induced cirrhosis in 6/8 animals without mortality. The histologic pictures differed somewhat in that the CCl₄ group exhibited more necrosis and cellular swelling while the thioacetamide group had more nuclear atypias and proliferation. Biochemically both groups had elevated plasma levels of aspartate aminotransferase. The lysosomal enzyme β-hexosaminidase (β-NAG) showed a transient increase in the thioacetamide animals, while β-glucuronidase decreased. CCU-induced cirrhosis led to an increase in β-NAG. Plasma zinc decreased in both groups as well as liver zinc content in the CCl₄ group, while there was a continuous elevation of liver zinc in the thioacetamide group. We conclude that oral administration of thioacetamide is a simple and reliable method of inducing experimental liver cirrhosis. The differences in histological appearances and some biochemical parameters may be caused by the different mechanisms of action of thioacetamide and CCl₄.

Under present environmental conditions, an increase in pollution owing to metals such as cadmium (Cd), lead (Pb), and methylmercury (MeHg) must be expected. The resulting effects would be seen particularly in the food chain. The daily intake of toxic metals in various parts of the world is different and depends on both the dietary habits and the concentration in foodstuffs. Oral ingestion of these toxic metals perturbs the metabolism of essential elements, especially zinc (Zn), copper (Cu), iron (Fe), and selenium (Se). The elemental composition of body tissues and fluids is an indicator of the nutritional and pathological status of humans. This review will describe the dietary intake and gut absorption of essential and toxic elements. Furthermore, it will discuss threshold values, toxic effects in relation to body burden of toxic metals, the biological indices of exposure, and the interaction between toxic and essential elements. The overall ratio of Cu, Zn, Fe, and Se concentration to Cd in the human kidney is the lowest in comparison to Hg and Pb. Increased kidney copper and urinary losses may be common denominators in the manifestation of renal toxicity induced by heavy metals. Factors affecting availability and loss of copper should be identified and measured. The critical kidney concentration for Cd, Pb, and MeHg should be revised in relation to essential elements.

A strict vegetarian diet [vegan diet (VD)] was investigated. Six middle-aged vegans (three men and three women) collected copies of 24-h diets using the duplicate portion sampling technique. By chemical analyses, the nutrient composition was determined in detail and compared with corresponding figures of a normal mixed Swedish diet. In the VD 30% of the energy originated from fat compared with 40% in normal Swedish mixed diet (MD). Linoleic acid was the dominant fatty acid (60% of total fat in VD versus 8% in MD). The VD contained 24 g protein/1000 kcal compared to 30 g/1000 kcal in MD, but the intake of essential amino acids by the vegans exceeded the recommendations. Dietary fiber was about 5 times higher in the vegan diet (29 versus 6 g/1000 kcal) and sucrose similar to MD (18 versus 21 g/1000 kcal). Among the inorganic nutrients the concentration of calcium (351 versus 391 mg/1000 kcal) and sodium (53 versus 49 mmol/1000 kcal) were similar in both types of diets but the amount of potassium (56 versus 30 mmol/1000 kcal, magnesium (300 versus 110 mg/1000 kcal), iron (9 versus 6.5 mg/1000 kcal), zinc (6.5 versus 4.7 mg/1000 kcal), and copper (2 versus 0.7 mg/1000 kcal) were nearly doubled. Iodine (39 versus 156 micrograms/1000 kcal and selenium (5 versus 17 micrograms/1000 kcal) were much lower in the VD, selenium even being undetectable in several 24-h diets. The VD was rich in folic acid (301 versus 90 micrograms/1000 kcal in MD) but the intake of vitamin B12 was only 0.3 to 0.4 microgram/day (MD: 3 to 4 micrograms/day). No clinical signs of nutritional deficiency were observed in the vegans. Serum protein levels of the vegans as well as their serum lipoproteins were near the lower range of the reference group. In addition, none of the vegans was overweight and their blood pressures were low for their age.

Carcinogenesis encompasses a prolonged accumulation of injuries at several different biological levels and include both genetic and biochemical changes in the cells. At each of these levels, there are several possibilities of intervention in order to prevent, slow down or even halt the gradual march of healthy cells towards malignancy. Diet modification is one such possibility. A number of natural foodstuffs, especially fruits and vegetables contain substantial quantities of molecules that have chemopreventive potential against cancer development. Such compounds include vitamins, trace elements and a variety of other molecules with antioxidant properties. Carotenoids, flavanoid polyphenols, isoflavones, catechins, and several other components that found in cruciferous vegetables are molecules that are known to protect against the deleterious effect of reactive oxygen species. A number of epidemiological and experimental studies have shown that vitamin C and E, Beta-carotene and the essential trace element selenium can reduce the risk of cancer. Consistent observations during the last few decades that cancer risk is reduced by a diet rich in vegetables, fruits, legumes, grains and green tea have encouraged research to identify several plant components especially phytochemicals that protect against DNA damage. Many of these substances block specific carcinogen pathways. Dietary supplements are part of an overall health program, along with a high intake of fruits and vegetables that help to combat damage to cells, which in turn may initiate cancer development. This paper will review current knowledge concerning diet modification and cancer prevention with special reference to minerals and trace elements.

Trace elements like copper, zinc, iron and selenium have a significant influence on the function of the immune system. We studied plasma levels of trace elements in 53 patients with acute bacterial and viral infections. In bacterial infections (septicaemia, pneumonia, erysipelas and meningitis) the plasma concentrations of selenium, iron and zinc were decreased. Plasma copper was unchanged in patients with erysipelas, but increased in other types of bacterial infections. Although the patients with viral infections showed similar shifts of the trace elements as were observed in patients with bacterial infections, the changes were not as pronounced. A plasma selenium value below 0.8 mumol/l was found in only 6% of the patients with viral infections in contrast to 63% of the patients with septicaemia or 57% of the patients with pneumonia. Furthermore, in viral infections 60% of the zinc values were below the mean level of 12.8 mumol/l observed in healthy controls as compared with 90% of the values in patients with sepsis or 92% of the values in patients with pneumonia. The onset of change in trace elements occurred within a few days and persisted for several weeks. These changes seem to be non-specific and are independent of the agent causing infection. The different types of infections were followed by changes in most of the plasma proteins which are known to be associated with an inflammatory reaction. The changes in plasma proteins were most pronounced in patients with sepsis and pneumonia. Patients with sepsis having a high degree of inflammation did not show a positive correlation between the severity of the disease--as judged by plasma proteins--and the alterations of trace elements.

SUMMARYThe redox cycling contact herbicide paraquat (PQ) causes oxidative damage to pulmonary tissue. PQ is reduced enzymatically to PQ radical in lung where it reacts with molecular oxygen, generating reactive oxygen species (ROS). ROS damage various macromolecules including DNA. However, the ability of paraquat to mediate DNA damage is unknown. In this study, Bam H1 site (5'-GGATCC-3') on pBR322 DNA was chosen as the target sequence for a study of the PQ-mediated DNA damage. The incubation of PQ with plasmid DNA in the presence of freshly prepared rat lung microsomes and NADPH resulted in damage to the restriction site. The PQtreated DNA was not digested with the endonuclease reflected by the digestion pattern of DNA on agarose gels. The effect was dependent on the dose of PQ. The PQ-mediated damage to DNA was comparable to DNA damage caused by ROS generated through the xanthine-xanthine oxidase system. The results of the present study suggest that ROS generated by PQ in vitro under aerobic conditions may lead to a modification of the restriction site on DNA.

Delta-aminolevulinic acid dehydratase (ALAD) is an enzyme involved in the biosynthesis of heme, in which it catalyzes the condensation of two molecules of delta-aminolevulinic acid to one molecule of porphobilinogen. It is a sulfhydryl enzyme, which means, among other things, that its activity is inhibited by many heavy metals. In the present investigation rabbits were given either zinc or lead or both. Zinc had a strong activating effect on ALAD in vivo, and the inhibitory effect of lead was almost completely eliminated. A close positive correlation was found between ALAD in the red blood cells and zinc in the plasma, but there was no correlation between ALAD and zinc in the red blood cells. These observations are of particular interest in the light of recent findings, suggesting that zinc is an essential metal for ALAD.