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The effects of certain chelating agents on some aspects of copper metabolism in rats and mice Wyse, David George


Plicatic acid and 5-isopropyltropolone, which are found in the heartwood of western red cedar (Thuja plicata, Donn), are known chelators of copper. A study has been made of their effects on some aspects of copper metabolism in rats and mice. As a basis of comparison similar experiments were carried out using penicillamine (PEN), a chelating agent with wide clinical use. In the experiments the sodium salt of 5-isopropyltropolone (T-Na) and the potassium salt of plicatic acid (P-K) were used. When administered daily, P-K and PEN caused an increase in urinary and fecal excretion of copper in rats on a normal diet and an increase in the level of copper in the liver and kidney and a decreased level of copper in the heart and brain. The increased urinary excretion is much more marked with PEN than with P-K. T-Na administered daily had no effect on the excretion of copper in rats on a normal diet and causes a rise in copper content of liver and kidney and a lowering of copper content of heart and brain. It appears that the copper level elevation in kidney and liver caused by P-K and PEN is due to an increased utilization of the routes of excretion while the increased level due to T-Na is probably due to deposition in the cells. When these compounds are administered daily to copper-fed rats similar observations were made with the difference that in organs where copper levels are increased the increases are greater and in organs where copper levels are decreased the decreases are smaller. With T-Na there is one marked difference in that the copper level in the brain is increased. It is felt that this increase is due to a greater penetrating ability of the T-Na-copper chelate because of its lipid solubility. P-K and PEN have very little effect on the toxicity of a single large dose of copper. Earlier experiments with T-Na showed that when T-Na is given shortly after a single large dose of copper the toxicity is greatly increased. The explanation of this is very likely that T-Na increases the penetration of the copper into the CNS and it is here that the toxic effect is exerted. It is felt that this is due to a solubility factor, T-Na and its chelate being lipld-soluble and P-K, PEN and their chelates being water-soluble. When T-Na, P-K and PEN are given to rats in small daily doses over a long period, the atria from such rats exhibited a reduced chronotropic response to tyramine. If at the same time as the rats are being given the chelating agent, they are given excess copper in drinking water the tyramine response remains close to normal. In this regard T-Na possesses the most activity. These observations support the theory that chelating agents inhibit dopamine-β-hydroxylase by rendering copper inaccessible to the enzyme and that subsequent to this inhibition the biosynthesis of the catecholamines is inhibited at the dopamine stage preventing the formation of norepinephrine and epinephrine. As the levels of endogenous norepinephrine and epinephrine fall, the result is a reduced tyramine response. If T-Na, P-K, PEN and D-Na are given in a large single dose the inhibition of dopamine-β-hydroxylase is not evident while it appears that COMT may be being inhibited.

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