metallothionein and Protein-Energy-Malnutrition

In this study, we compared results obtained in protein calorie malnourished (PCM) monkeys and controls given Cd2+ (5 mg Cd2+/kg body wt./day) orally for 24 weeks. After 16 weeks of Cd2+ exposure, an indolent renal failure develops in PCM monkeys which resulted in significant increase in urinary excretion of total protein, Cd2+, Zn2+ and Ca2+ as compared to corresponding to Cd(2+)-treated control group. In isolated proximal tubule brush border membrane vesicles (BBMV), Cd2+, Zn2+ and Ca2+ transport were significantly impaired in Cd(2+)-exposed PCM monkeys as compared to Cd(2+)-treated controls. The mechanism of higher urinary excretion of Cd2+, Zn2+ and Ca2+ was examined by analyzing the kinetic parameters of transport systems. The kinetic studies of Cd2+, Zn2+ and Ca2+ transport systems in the BBMV preparations of Cd(2+)-exposed PCM monkeys exhibited a significant decrease in Vmax and an appreciable increase in Km as compared to Cd(2+)-treated controls. These findings suggested that Cd2+ treatment of PCM monkeys caused either a decrease in the number of transporters in the brush border membrane or an increase in the number of less active transporters for Cd2+, Zn2+ and Ca2+. Furthermore, brush border membrane-bound enzymes, viz. alkaline phosphatase and leucine aminopeptidase, activities were significantly impaired in Cd(2+)-exposed PCM monkeys. Cadmium content in kidney cortex of Cd(2+)-exposed PCM monkeys was 3.34-fold higher than Cd(2+)-exposed controls. These findings also established that Cd2+ not bound to metallothionein (MT) was significantly higher in Cd-exposed PCM monkeys, which may be an important determinant in renal toxicity by interacting with sensitive sites in the renal cells and causing renal damage in Cd-exposed PCM monkeys.

Topics: Administration, Oral; Alkaline Phosphatase; Analysis of Variance; Animals; Biological Transport; Cadmium; Calcium; Diet, Protein-Restricted; Kidney; Kidney Cortex; Kinetics; Leucyl Aminopeptidase; Macaca mulatta; Male; Metallothionein; Microvilli; Protein-Energy Malnutrition; Proteinuria; Renal Insufficiency; Zinc

A monkey model has been set up for protein calorie malnutrition and calcium deficiency. Oral exposure of 5ppm Cd/kg body wt./day for 24 weeks led to increased excretion of Cd, metallothionein (MT) and zinc. Rehabilitation of PCM monkeys for one year resulted in gradual reduction and finally complete disappearance of urinary metallothionein. During Cd exposure, the accumulation of Cd and induction of MT was significantly higher in liver, kidney and intestine. MT was also induced in heart, lung and testis of Cd exposed PCM and calcium deficient monkeys. Metallothionein from liver has been resolved into three isoforms, viz MTa, MTb and MTc on DEAE-Sephadex A 25 ion exchange column. MTc is the major isoform in Cd-treated, normal and protein calorie malnourished monkeys whereas MTb is the major isoprotein in the cadmium treated calcium deficient monkeys. The iso-metallothioneins varied in their metal composition in the nutritional stress conditions and showed different capacities to reactivate apo-enzymes viz. alkaline phosphatase, ceruloplasmin, superoxide dismutase and glutathione peroxidase. Thus, metallothionein plays a key role in metal metabolism during cadmium toxicity under nutritional stress conditions.

Topics: Alkaline Phosphatase; Animals; Cadmium; Calcium; Chromatography, Gel; Copper; Drug Tolerance; Inactivation, Metabolic; Intestinal Mucosa; Kidney; Liver; Macaca mulatta; Metallothionein; Protein-Energy Malnutrition; Zinc

Metallothionein (MT) a low molecular weight, Cd-binding, cysteine rich, cytosolic protein has been isolated, purified and characterized from cadmium exposed Rhesus monkeys maintained on protein calorie malnourished (PCM) diet. Metallothionein was resolved into three isoforms i.e. MTa, MTb and MTc. The ratio of Cd, Zn and Cu varied in these isometallothioneins. MTc was the major isometallothionein. U.V. Spectra of MTc revealed the presence of mercaptide bonds and absence of aromatic amino acids. These observations were further confirmed by amino acid analysis of MTc which demonstrated high cysteine content (22.6) followed by serine, glycine and lysine. The molecular weight of MTc as determined by gel filtration and amino acid analysis was 13,000 and 6398 daltons respectively. This demonstrates that MTc is a nonglobular ellipsoid polypeptide. MTc showed a unique property of binding selenium. Monkey liver metallothionein was immunologically identical with human metallothionein. All the characteristics of MTc obtained in the present study reveal a similarity between monkey and human metallothionein probably due to closer phylogenetic relationship between the two species.

Topics: Amino Acids; Animals; Cadmium; Chromatography, Gel; Chromatography, Ion Exchange; Immunodiffusion; Liver; Macaca mulatta; Male; Metallothionein; Molecular Weight; Protein-Energy Malnutrition

Oral administration of cadmium results in the induction of metallothionein in liver of rhesus monkeys subjected to protein calorie malnutrition and calcium deficiency. Metallothionein was resolved into three iso-proteins viz. MTa, MTb & MTc which varied in their quantities and metal composition in these nutritional stress conditions. 'MTc' was the major iso-protein in protein calorie malnourished monkeys, while 'MTb' predominated in the calcium deficient group.

Topics: Animals; Cadmium; Cadmium Poisoning; Calcium; Cytosol; Liver; Macaca mulatta; Male; Metallothionein; Protein-Energy Malnutrition

Induction of cadmium metallothionein (MT) in chronic cadmium exposure in Rhesus monkeys undergoing protein calorie malnutrition (PCM) and calcium deficiency has been studied. A positive correlation between cadmium content and levels of MT in kidney, liver, intestine, testis, heart and lung, has been observed. The accumulation of cadmium and synthesis of MT in these tissues was highest in monkeys subjected to cadmium exposure during calcium deficiency. Although more of cadmium is directed towards kidneys of calcium-deficient monkeys the MT-inducing ability of kidney is lower than that of liver. Monkeys on PCM diet also showed enhanced accumulation of cadmium and MT as compared to those on normal diet during cadmium exposure.

Topics: Animals; Cadmium Poisoning; Calcium; Diet; Macaca mulatta; Male; Metallothionein; Protein-Energy Malnutrition; Tissue Distribution