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Biomedical subjects

M A Lea

Publications and source records attributed to M A Lea.

At least 73 records · Page 4Linked to original sources
PubMed1977

Divergent effects of cyanate on amino acid and phosphate uptake by liver and hepatoma.

The uptake of alpha-aminoiso[3H]butyric acid and 32Pi was observed to be inhibited by sodium cyanate in transplanted hepatomas but was increased in the livers of the tumor bearing rats. Incorporation of 32Pi into macromolecules in hepatomas was also inhibited by cyanate. Treatment with this drug did not influence circulating concentrations of isotope-labeled materials. There were relatively small effects on uptake of 36Cl- in cyanate-treated rats and the action was not tissue specific. The data were compatible with an inhibitory effect of cyanate on active transport in hepatomas which was not seen under the same conditions in host liver.

Aminoisobutyric Acids↗
PubMed1976

Inhibition of glycolytic enzymes of rat liver and hepatomas by free fatty acids.

The action of free fatty acids on glycolytic enzymes was compared in normal and neoplastic tissues. Preincubation of tissue supernatant fractions with octanoate or laurate caused an inhibition of the activities of hexokinase and phosphofructokinase. An inhibition was also observed of lactate production with either glucose or glucose 6-phosphate as substrate. A similar degree of inhibition was observed for actions on normal liver and kidney, on the 7800 and 3924-A hepatomas and on the MK-3 renal cortical tumor. The possible relationship between the inhibition of glycolytic enzymes by fatty acids and anti-tumor activity previously observed with these compounds was noted.

Animals↗
PubMed1976

Decreased uptake of orotate in kidney tumors.

The uptake of isotope by three transplanted kidney tumors after i.p. injection of 3H-labeled orotate was less than 5% of that in the host kidney cortex. A decrease of similar magnitude in the uptake into the acid-soluble tissue fractions from the kidney tumors was observed with very low incorporation into RNA relative to the host kidney cortex. Total uptake of orotate-3H and incorporation into RNA were several fold higher in the normal kidney cortex than in the kidney medulla and for the kidney cortex both parameters were less in young than in old rats. The uptake of uracil-3H by two kidney tumors was approximately 40% of that in the kidney cortex of host rats. Although the uptake of orotate-3H in kidney cortex was greater than that for uracil-3H the reverse situation was observed with kidney tumors, indicating that renal neoplasia in the rat is accompanied by an altered pattern of uptake of these metabolites.

Animals↗
PubMed1976

Binding of metabolically activated benzo(a)pyrene to nuclear macromolecules.

The binding of metabolically activated [3H]benzo(a)pyrene ([3H]BP) to the DNA, RNA, histones, and nonhistones of isolated rat liver and lung nuclei was studied. Conditions for optimal binding to the nuclear components were determined. Upon incubation with isolated liver nuclei and reduced nicotinamide adenine dinucleotide phosphate, [3H]BP was able to bind to nuclear components. The binding appeared to be covalent in nature. Treatment of the rats with 3-methylcholanthrene induced the nuclear aryl hydrocarbon hydroxylase (AHH) activity and also increased the level of carcinogen binding. The addition of rat liver microsomes to the incubation systems greatly enhanced the level of [3H]BP binding to the macromolecules in the nuclei from both the control and 3-methylcholanthrene-treated rats, and the maximal levels of binding obtained with these two types of nuclei were similar. The binding was inhibited by 7,8-benzoflavone or glutathione. Lung nuclei from control rats had very low AHH activity and did not exhibit appreciable carcinogen binding, whereas those from 3-methylcholanthrene-pretreated animals had slightly higher AHH activity and caused low levels of binding. The binding of [3H]BP to lung nuclei was greatly enhanced by liver microsomes but only slightly by lung microsomes, which had rather low AHH activity. Several lines of evidence indicate that, in the control experiments (no reduced nicotinamide adenine dinucleotide phosphate added), the radioactivity associated with the macromolecule fractions is probably a background value rather than due to the binding caused by a specific interaction between benzo(a)pyrene and cytochrome P-450. The present study clearly demonstrates that a carcinogen activated at the microsomes can enter into the nucleus and react with its macromolecules; the carcinogen can also be activated by the monoxygenase system of the nuclear envelope. It appears that both the endoplasmic reticulum and the nuclear envelope are potentially important sites of carcinogen activation.

Animals↗
PubMed1976

Actions of exogenous histones and other proteins on [3H]-thymidine incorporation into DNA of Novikoff hepatoma cells.

The effects of exogenous proteins on the incorporation of [3H]-thymidine into DNA was studied in Novikoff hepatoma ascites cells incubated in Eagle's minimal essential medium. A liver cytosol fraction (8 mg protein/ml) caused approximately 80% inhibition of isotope incorporation. The inhibitory activity of cytosol fractions from Morris hepatomas 9618A2, 5123C, and 20 were inversely related to their growth rate. Under conditions in which there appeared to be a density dependent inhibition of growth, a mean 10-20% stimulation of isotope incorporation was observed after addition of total calf thymus histones and individual fractions in the concentration range of 100-400 microgram/ml. In experiments with lower cell concentrations, a 60% or greater increase in [3H]-thymidine incorporation could be obtained with total calf thymus histone and with F1 and arginine-rich histones from rat liver. At concentrations of 1-2 mg/ml, histones inhibited DNA synthesis. Bovine serum albumin had little effect on DNA synthesis. Polylysine caused an 80-90% inhibition at a concentration of 1 mg/ml, but stimulatory effects were detected under certain conditions at 10 microgram/ml. The results suggest critical dependence on the ratio of cell and exogenous protein concentration in the action of proteins on DNA synthesis.

Animals↗
PubMed1975

Tumor-selective inhibition of the incorporation of 3H-labeled amino acids into protein by cyanate.

Sodium cyanate at a dose level of 125 or 250 mg/kg i.p. caused an inhibition of incorporation of 3H-labeled amino acids into cytoplasmic and nuclear proteins of the rapidly growing hepatoma 7777 and the slowly growing hepatoma 9618A. There was no inhibitory effect on 3H-labeled amino acid incorporation into protein in the livers of rats bearing these tumors. Studies on the effects of sodium cyanate on incorporation of 3H-labeled amino acids into total acid-insoluble material indicated that a greater than 85% inhibition could be achieved in hepatoma 5123C, hepatoma 9618A2, and the MK3 kidney tumor with either little or no effect in host liver, kidneys, brain, skeletal muscle, intestinal mucosa, and regenerating liver after partial hepatectomy.

Amino Acids↗
PubMed1975

Fractionation of nuclei and analysis of nuclear proteins of rat liver and Morris hepatoma 7777.

The contributions of nuclear populations to the total profile of nuclear proteins in a tissue were examined in normal rat liver and Morris hepatoma 7777. Comparison by sodium dodecyl sulfate polyacrylamide gel electrophoresis of phenol-soluble nuclear proteins from tumor and control liver revealed additional proteins of molecular weight 60,000, 100,00, and 135,000 and the loss of proteins of about 45,000 and 55,000 in the tumor. Subfractionation of liver nuclei on a 30 to 50% sucrose gradient yielded three nuclear classes with nearly identical complements of the phenol-soluble proteins. Similar fractionation performed on the hepatoma nuclei also produced three nuclear populations. In the hepatoma nuclei, several differences in the phenol-soluble proteins were found between the minor, slowly sedimenting nuclear fraction, and the two major fractions, while the two latter fractions were very similar in their protein composition. Histones derived from both tissues were also compared electrophoretically, indicating a decrease in the concentration of histone H1(0)in all nuclear classes derived from the tumor.

Animals↗
PubMed1975

Nuclear protein changes in rat hepatomas correlating with growth rate.

The nature of nuclear proteins that are soluble in 8 M urea-50 mM phosphate, pH 7.6, was compared in rat liver and Morris hepatomas, Isoelectric focusing, using carrier ampholytes for a pH gradient of 3.5 to 10, indicated that with increasing growth rate of the hepatomas there was a progressive tendency for a decrease in nonhistone nuclear proteins with isoelectric points in the range 7.5 to 8.9 and an increase in the range 5.1 to 6.7. Studies on the influence of time on the pH gradient revealed that a nonuniform drift provided a better resolution of the pH range 7.5 to 8.9 at 7 hr than at 24 hr, while the latter time for electrofocusing gave an improved resolution of the pH range 5.1 to 6.7 Polyarcylamide gel electrophoresis in a urea-acetic acid system showed that 8 M urea-50 mM phosphate; pH 7.6 extracted a small part of the histones from nuclei of both liver and hepatomas. There was less extraction of histones from the hepatoma nuclei, especially in two rapidly growing hepatomas with the most notable difference being seen in the lysine-rich H1 histone. The results suggested that in addition to qualitative or quantitative changes in nonhistone nuclear proteins in liver cancer there are alterations in the binding of histones to chromatin.

Acetates↗