Biliary copper excretion by hepatocyte lysosomes in the rat. Major excretory pathway in experimental copper overload
We investigated the hypothesis that lysosomes are the main source of biliary copper in conditions of hepatic copper overload. We used a rat model of oral copper loading and studied the relationship between the biliary output of copper and lysosomal hydrolases. Male Sprague-Dawley rats were given tap water with or without 0.125% copper acetate for up to 36 wk. Copper loading produced a 23-fold increase in the hepatic copper concentration and a 30-65% increase in hepatic lysosomal enzyme activity. Acid phosphatase histochemistry showed that copper-loaded livers contained an increased number of hepatocyte lysosomes; increased copper concentration of these organelles was confirmed directly by both x ray microanalysis and tissue fractionation. The copper-loaded rats showed a 16-fold increase in biliary copper output and a 50-300% increase in biliary lysosomal enzyme output. In the basal state, excretory profiles over time were similar for biliary outputs of lysosomal enzymes and copper in the copper-loaded animals but not in controls. After pharmacologic stimulation of lysosomal exocytosis, biliary outputs of copper and lysosomal hydrolases in the copper-loaded animals remained coupled: injection of colchicine or vinblastine produced an acute rise in the biliary output of both lysosomal enzymes and copper to 150-250% of baseline rates. After these same drugs, control animals showed only the expected increase in lysosomal enzyme output without a corresponding increase in copper output. We conclude that the hepatocyte responds to an increased copper load by sequestering excess copper in an increased number of lysosomes that then empty their contents directly into bile. The results provide direct evidence that exocytosis of lysosomal contents into biliary canaliculi is the major mechanism for biliary copper excretion in hepatic copper overload.
- Research Organization:
- Mayo Medical School, Clinic, and Foundation, Rochester, MN (USA)
- OSTI ID:
- 6495999
- Journal Information:
- J. Clin. Invest.; (United States), Vol. 83:1
- Country of Publication:
- United States
- Language:
- English
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59 BASIC BIOLOGICAL SCIENCES
COPPER
METABOLISM
HYDROLASES
ENZYME ACTIVITY
ACID PHOSPHATASE
BILE
BIOLOGICAL MODELS
BIOLOGICAL PATHWAYS
ELECTRON MICROPROBE ANALYSIS
EXCRETION
LIVER CELLS
LYSOSOMES
RATS
ANIMAL CELLS
ANIMALS
BIOLOGICAL MATERIALS
BODY FLUIDS
CELL CONSTITUENTS
CHEMICAL ANALYSIS
CLEARANCE
ELEMENTS
ENZYMES
ESTERASES
MAMMALS
MATERIALS
METALS
MICROANALYSIS
ORGANOIDS
PHOSPHATASES
RODENTS
SOMATIC CELLS
TRANSITION ELEMENTS
VERTEBRATES
560300* - Chemicals Metabolism & Toxicology
550501 - Metabolism- Tracer Techniques