David M. Foster

Metabolism of high-density lipoprotein apolipoproteins in Tangier disease.

To define the metabolic defect in Tangier disease, we studied the kinetics of [125I]-high-density lipoprotein apolipoproteins (apolipoproteins A-I and A-II) in 11 normal subjects, two obligate heterozygotes, and two homozygotes. Mean synthesis of apolipoproteins A-1 and A-11 was 8.24 mg per kilogram per day in the normal group, 7.94 in heterozygotes and 3.66 in homozygotes. The mean plasma-residence time for both apolipoproteins was 5.21 days in the normal subjects, 3.41 days in heterozygotes, and 0.52 days in homozygotes. In normal subjects and heterozygotes the apolipoproteins were catabolized at similar rates, whereas in homozygotes apolipoprotein A-I was catabolized at a much greater fractional rate than apolipoprotein A-II. These findings indicate that the deficiency of these apolipoproteins in Tangier disease is largely due to rapid and altered catabolism.

The composition and metabolism of high density lipoprotein subfractions

The composition and metabolism of high density lipoprotein (HDL) subfractions were investigated in seven nomal individuals. Mean HDL2 (d, 1.063–1.125 g/ml) composition (by weight) was 43% protein, 28% phospholipid, 23% cholesterol, and 6% triglyceride, and mean HDL3 (d, 1.125–1.21 g/ml) composition was 58% protein, 22% phospholipid, 14% cholesterol, and 5% triglyceride. The mean apoA-I; apoA-II weight ratio was 4.75 for HDL2 and 3.65 for HDL3.HDL2 protein was proportionally slightly richer in C apolipoproteins and higher molecular weight constituents (including apoE) than HDL3. Kinetic studies utilizing radiolabeled HDLA (d, 1.09–1.21 g/ml), HDL2, and HDL3 demonstrated rapid exchange of apoA-I and apoA-II radioactivity among HDL subfractions, similar fractional rates of catabolism of apoA-I and apoA-II within HDL, and similar radioactivity decay within HDL subfractions. Mean plasma residence time was 5.74 days for radiolabeled HDL2 and 5.70 days for radiolabeled HDL3. Differences in HDL protein mass among individuals were largely due to alterations in catabolism, and in general both HDL2 and HDL3 were catabolized via a plasma and a nonplasma pathway. Data from simultaneous radiolabeled very low density lipoprotein and HDL studies in 2 individuals are consistent with the concept that apoC-II and apoC-III are catabolized at a different rate than are apoA-I and apoA-II within the HDL density range.

Effects of oral zinc loading on zinc metabolism in humans II: In vivo kinetics

The effects of oral zinc loading on zinc metabolism were studied in 10 patients with taste and smell dysfunction following oral administration of Zn-65 (physical t1/2 = 245 d) and subsequent administration of oral stable zinc. Patients took an ad libitum dietary zinc intake of 8-13 mg daily for 290-440 days (mean, 336) following Zn-65 administration, followed by an intake of an additional 100 mg/day of zinc ion (as ZnSO4) over the next 112-440 days (mean, 307). A previously developed compartmental model, based on five day studies of patients with taste and smell dysfunction, was extended in such a way that it was consistent with both short term and long term kinetics. In this extended model, the turnover of 90% of total body zinc, previously unaccounted for by the kinetics in the short term studies could be explained by a single compartment, as postulated in the short term studies. Using the model, it was found that changes in the rate constants for gastrointestinal absorption and renal excretion of zinc were both necessary and sufficient to explain the changes seen in the kinetic curves following oral zinc loading. Michaelis-Menten type saturation mechanisms were adequate to explain the observed parameter changes. These changes also accounted for the observed mean plasma zinc mass increase of only 37% above pre-load levels in face of an 11-fold increase in zinc intake.

Zinc metabolism in adrenal cortical insufficiency: effects of carbohydrate-active steroids.

Detailed studies of zinc kinetics were performed in two patients with adrenal cortical insufficiency to investigate the effects of carbohydrate-active steroids (CAS) on zinc metabolism. Zinc- 69m was administered intravenously to each patient under two conditions: (1) treated with CAS replacement therapy and (2) untreated, ie, without hormone treatment for five to six days. Radioactivity was measured in blood plasma, red blood cells, urine, and stool and by means of external probes placed over liver and thigh. Data were analyzed using a previously developed multicompartmental model, which describes the early phase of zinc metabolism. The results of these studies suggest that CAS promotes the internalization of zinc into red blood cells and liver cells. These results are consistent with previous in vitro and in vivo studies in which CAS was shown to induce the synthesis of metallothionein in liver cells.

Effects of oral zinc loading on zinc metabolism in humans—I: Experimental studies

The effects of oral zinc on distribution, retention and excretion of orally administered 65Zn were studied in 50 patients with taste and smell dysfunction. The study was conducted in three phases. In the first phase all patients were studied for 21 days after receiving 3-18 microCi of 65Zn as ZnCl2 orally after an overnight fast. In the second phase, started after 21 days and continued for 290 to 440 (mean 336) days, all 50 patients received placebo for ZnSO4. In the third phase 14 patients continued on placebo while 36 received ZnSO4 (100 mg/day Zn++) for 112 to 440 (mean 307) days. Phases two and three were a controlled clinical trial of the effects of zinc on retention of 65Zn tracer. Total body retention and activity in plasma and red cells were measured for all patients throughout the study. Ten of the 36 patients treated with ZnSO4 had additional measurements of 65Zn activity in liver and thigh made using external detectors. Total body retention during the second phase placebo period was not significantly different (p greater than 0.25) for the 36 subjects subsequently treated with ZnSO4 (biological half-time (Tb) 378 +/- 12 days) (mean +/- SEM) and the 14 who were continued on placebo through the third phase of the study (Tb = 384 +/- 8 days). During the third phase patients receiving ZnSO4 showed an accelerated loss of total body 65Zn (Tb = 235 +/- 8 days) which was significantly different (p greater than 0.001) from half-time values during placebo treatment. Accelerated loss of 65Zn from the thigh was apparent immediately while that from the liver began after a mean delay of 107 days. There was no apparent effect of zinc on loss of mean 65Zn activity from red blood cells.

Multiple zeros for eigenvalues and the multiplicity of traps of a linear compartmental system

Abstract It is known that a linear compartmental system has a trap if and only if the associated system of differential equations has zero as an eigenvalue. In this paper, we show that if such a system has zero as an eigenvalue of multiplicity m, then the system contains m irreducible traps.

A high affinity site for sugar transport at the inner face of the human erythrocyte membrane

A disagreement centering on a method of analysis as to the existence of a high affinity site for glucose transport at the inner face of the human red cell membrane is resolved by using direct fitting methods to confirm the original parameter estimates.

The methodology of compartmental modeling as applied to the investigation of lipoprotein metabolism

The statements to this point only give a cursory review of the beginning (20 years) of the kinetic approach to the classification of lipoproteins and subsystems which are involved in their synthesis and metabolism. At the present time the following partial list of theoretical findings expressed through model building can be made for the lipid and lipoprotein field: A cascade process of delipidation for VLDL exists and the rate of this process is decreased in subjects with hyperlipoproteinemia. ApoC recycles between VLDL and HDL in response to the dynamics of the delipidation cascade. New synthesis of apoB first appears with newly synthesized VLDL. VLDL apoB synthesis decreased in hyperlipidemic states examined. Multiple synthesis pathways exist for the triglyceride moiety of VLDL as determined by the transit time of a precursor through the conversion pathway. Thus the isotopic precursor methods now yield the same results as the more invasive techniques. Kinetic heterogeneity of VLDL, IDL, LDL, and HDL has been established. Kinetic heterogeneity for apoA-I, apoA-II, apoB, apoC-2 and apoC-3 have been established. The presence of direct pathways for IDL and LDL synthesis have been established. Irreversible loss of apoC from HDL has been predicted using models. Synthesis of apoC has been found to be invariant in hyperlipoproteinemic states studied. Hepatic cholesterol compartments associated with the formation of bile acids and biliary cholesterol derive a majority of their cholesterol from newly synthesized and lipoprotein-free cholesterol. More than 85% of the free cholesterol in the beta-lipoproteins cycles directly through the HDL. Free cholesterol recycles between HDL and tissue pools and between HDL and beta-lipoproteins.(ABSTRACT TRUNCATED AT 250 WORDS)