Biomedical subjects
Publications and source records attributed to A Petkau.
Factors are identified that influence the initiation, propagation, and efficiency of free-radical processes, or that ameliorate or mask them. Major biochemical disruptions of the ischemic myocardium or the central nervous system are cited for their underlying free-radical reactions. Encouraging attempts at rational therapy of disease having a free-radical component are referenced.
The effect of superoxide dismutases from five species upon phospholipid bilayers has been investigated. The uptake by egg phosphatidylcholine bilayers of the holo and apo forms of bovine superoxide dismutase increases with enzyme concentration and only a fraction of each is removed by treatment with trypsin. These uptake data indicate that both forms of the enzyme associate with and are embedded within lipid bilayers. From the spectrum of the spin label 2-(3-carboxypropyl)-4,4-dimethyl-2-tridecyl-3-oxazolidinyloxyl, the binding of superoxide dismutase to egg phosphatidylcholine bilayers can be shown to disorder the lipid packing. The disordering by the bovine holoenzyme is small but increases with increasing enzyme concentration and period of incubation. The disordering effects of the apoenzyme are much larger and are reversible by Cu2+, Zn2+ reconstitution of the apoenzyme. The disordering effect of the apoenzyme is further confirmed by differential scanning calorimetry. The gel to liquid crystalline phase transition of egg phosphatidylcholine is lowered 7 degrees C by 25% by weight apo-superoxide dismutase to lipid. Human, dog, swordfish and yeast superoxide dismutases also disorder, and to a greater extent than the bovine enzyme. The greatest perturbation is produced by yeast superoxide dismutase; a 20% decrease in the order parameter by 50% by weight enzyme to lipid.
The inactivation yield of superoxide dismutase (superoxide: superoxide oxidoreductase, EC 1.15.1.1) from bovine erythrocytes, when Co60-gamma-irradiated in air, N2 or N2O-saturated solutions, increases exponentially with the initial enzyme concentration. In aerated solutions at less than or equal to 10 micrometers, the inactivation process continues in a concentration-dependent manner in the subsequent 72 h. This post-irradiation effect is inhibited by catalase. Above 10 micrometers, radiation-induced inactivation of the enzyme is partially reversed in a concentration-dependent manner and is not affected by catalase. In aerated and N2O-saturated solutions, competitive scavenging of radiation chemical species by catalase and EDTA in combination reduces the inactivation yield by 80%; the residual yield remains dependent on enzyme concentration. Radiation-induced loss of copper and zinc initially exhibits a linear dose-response relationship and is less severe than the drop in enzyme activity.
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Radiation damage in phospholipid membranes involves free radical chain reactions which propagate on their own. These reactions oxidize the constituent fatty acids (LH) to alkyl radicals (L) which upon oxygenation, for lipid hydroperoxides (LOOH), some of which absorb light at 232 nm. The response (R) of these membranes to irradiation from tritium (3H) in tritiated water increases with dose (D) in accordance with R = aDm, where m = 1.44 +/- 0.30 in the absence of superoxide dismutase and 0.80 +/- 0.14 in its presence. The parameter "a" is expressible in terms of dose rate (delta D/delta t) by a = c (delta D/delta t)-n, where n = 1.18 +/- 0.05 in the absence of superoxide dismutase and 0.82 +/- 0.02 in its presence. Thus, R = cDm(delta D/delta t)-n where the values of m, n depend on the presence or absence of the free radical scavenger, superoxide dismutase. From this composite relationship, the response per annum for 100-250 millirem/y is calculable and found to differ qualitatively, that is, in the absence of superoxide dismutase the response increases whereas in the enzyme's presence it decreases. The latter trend is reminiscent of the correlation between radiation dose rate and the per annum malignant rate in humans. This coincidence is interesting in that LOOH are linked in the literature to several forms of carcinogenesis.
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In female Sprague Dawley rats, the tissue protein is homogeneously distributed and significantly increased in 7,12-dimethylbenz[a]anthracene-initiated mammary carcinoma. At the centre and margin of the carcinoma, the concentration of superoxide dismutase is 54 +/- 10 and 117 +/- 38 microgram/g, respectively, while in the tumour as a whole it is 104 +/- 32 microgram/g. The latter value is not significantly different from 113 +/- 35 microgram/g, the enzyme concentration in mammary tissue from lactating rats. Exposure of the tumour-bearing rats to hyperoxia does not increase the tumour protein but raises the enzyme concentration at the centre and margin of the carcinoma to 162 +/- 73 and 286 +/- 103 microgram/g, respectively.
1. Hydroperoxide formation in model membranes was measured via the net increase in absorbance at 232 nm after exposure to X-rays or 137Cs gamma rays in the presence and absence of bovine superoxide dismutase and other radical scavengers. 2. Membranes X-irradiated in air to 4200 rad at 210 rad/min exhibited a large increase in absorbance, a major portion of which was O2--mediated since active superoxide dismutase at 1 mug/ml reduced it by more than 80% to the level observed in N2O. In N2 the change in absorbance was smaller than in N2O but not in proportion to the halving in OH production. 3. The net absorbance of membranes exposed to a constant dose from 137Cs increased with decreasing dose rate. A minor component of this effect was due to exposure protraction with decreasing dose rates while the major component was attributed to long chain reactions initiated by ionizing radiation. A corollary effect was also observed, namely, that with reducing dose rate the dose required to elicit a constant absorbance change decreased. Both aspects were abolished by superoxide dismutase at 1 mug/ml. 4. The enzyme protected membranes after an acute exposure and from low level radiation at natural background while its inactivated form sensitized.
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Intravenously injected 125I-bovine superoxide dismutase in mice is essentially cleared from organs in 24 h. The 125I activity per g of tissue at 1 h varies among organs with the brain and kidneys showing the lowest and highest levels, respectively. Within tissues, degradation occurs so that, at 1 h after administration, 5-74% of the 125I activity remains associated with the enzyme, depending on the tissue. A small amount of the labelled enzyme is found in washed cells of thymus, lung, spleen, liver and brain.
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