Manganese Metabolism in Man: Rapid Exchange of MN56 with Tissue as Demonstrated by Blood Clearance and Liver Uptake1

Abstract

Despite the well-known physiological importance of manganese (1-7) and its implication in some disease states (2,(8)(9)(10), the exact nature of its metabolic role remains undefined (11,12).In mammals manganese concentrates in organs rich in mitochondria, notably the liver (2-7, 11, 13, 14); and previous work from this group (11) has shown these organelles to be the major pool of radiomanganese turnover shortly after injection into animals. In vitro traces of the element have widespread biochemical activity (2,3,(15)(16)(17)(18)(19), especially in relationship to mitochondria (20) and those of their enzyme systems that carry out oxidative phosphorylation (16,(21)(22)(23)(24)(25)(26).The present study of blood clearance and of radiation measured at the body surface following Mn" injection in man is an attempt to describe and to determine the kinetics of this turnover, which appears to correlate with mitochondrial function. From the analysis of these data in relation to the work of others it is also possible to gain insight into the mechanisms of transport directly from the blood. Our results further suggest that most of the normal body manganese is readily exchangeable and is not bound in metalloproteins or other highly stable configurations. EXPERIMENTAL Radioisotopic tracer. Mn" (half-life: 2.58 hr.) 2 was generated in the Brookhaven research reactor. One ml. aliquots containing 11.1 ,g. of MnSOgH2O (3.6 ,ug. of Mn' 3 were injected into patients. The radiation decay of other aliquots was followed for 48 to 72 hours with a well-type NaI(Ti) scintillating crystal and scaling circuit. The resultant activity curves indicated the only contaminating radioelement to be a small amount of Na' (about 0.5 per cent of the Mn' activity at injection time), which was ignored in the subsequent treatment of the data.Route of administration and withdrawal of blood samples. Following an overnight fast, patients received Mn" tracer intravenously. Thereafter serial venous blood samples of approximately 3 ml. volume were withdrawn from the contralateral arm. Samples were promptly assayed for radioactivity and weighed. Corrections for radioactive decay were then made. Frequent samples were obtained during the first few minutes after injection, but later sampling frequency was decreased gradually to intervals of approximately five minutes. Surface counting technique. Concurrently with thewithdrawal of blood samples, radiation was monitored over the body surface with collimated detectors whose outputs were transcribed automatically.4 As anticipated from animal data (2, 4-7, 11), preliminary scanning following Mn' injection revealed localization of the greatest radioactivity in the region of the liver. Accordingly, one scanner was positioned on the skin surface over the liver area, usually about 3 cm. above the costal margin in the right midclavicular line ("liver area" counter). A second counter was located over the right femur about 18 cm. above the patella ("thigh" counter). This was taken to be a "reference area" that would not...

T1 efficacy of EVP‐ABD: A potential manganese‐based MR contrast agent for hepatic vascular and tissue phase imaging

“…The blood T1 response of EVP-ABD was consistent with the previously observed multiexponential kinetics of Mn in blood (23,24). This confirmed that EVP-ABD behaved kinetically like free Mn in blood and explained its strong vascular enhancing capability resulting from the large molar relaxivity of Mn in blood (15,23).…”

“…A previous study (22) confirmed that, as seen for Mn alone (23,24), the initial distribution of EVP-ABD from the blood was rapid. To follow such a T1 response pattern, we used a single-shot turbo-FLASH sequence at a single TI to achieve sufficient temporal resolution through the first 8 minutes post contrast injection.…”

“…An additional 14% of the dose is eliminated with a half-life of 2.65 minutes, and the final 1% is eliminated with a half-life of 29.8 minutes (23). To determine whether the kinetics of Mn administered as EVP-ABD (160 mg% Mn, or 160 mg/100 mL) followed the same kinetics reported previously, EVP-ABD (Eagle Vision Pharmaceutical Corp., Exton, PA) was prepared according to the methods described in Harnish et al (21) and injected intravenously at 10 mol/kg as a 15-second bolus (83% of the dose), followed by up to a 30-second steady infusion (17% of the dose).…”

Changes in Enzymes (GOT and GDH) and Metals (Zn, Mn, and Mg) in Liver of Rats During Endocrine Imbalance and Caloric Restriction

“…Zinc may act as a cofactor for some of the dehydrogenase enzymes, and Mg is involved in many enzymatic reactions. The major fraction of Mn in the parenchymal cell of liver is present in mitochondria, and the remainder is found in microsomes and nucleus [2,151. Zinc is primarily found in cytoplasm [16].…”

“…In a previous study 161, it was found that this ratio was increasing at 2 1 days of age, although in muscle, the ratio was constant at 3, 5, and 8 weeks of age. If Mn is a measure of mitochondrial mass in the liver [2], this mass may reach constancy shortly after weaning. The value found for Mn was 0.74 pg per mg of DNA in liver, while the range of the RNA:DNA ratio was only 3.7 to 4.0 mg per mg of DNA from 26 to 49 days of age.…”