KINESIOL 1Y03 Lecture Notes - Lecture 13: Proteinuria, Haplotype, Basal Ganglia
23 Jun 2018
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Wilson’s disease
= a classic example of endogenous drug toxicity
Copper (found in nuts and mushrooms) = a trace element required for essential enzyme function
Examples =
superoxide dismutase (free radical detoxification)
Lysyl oxidase
Dopa-b-hydroxlase (neurotransmitter synthesis)
Tyrosinase
Cytochrome c oxidase (oxidative metabolism)
Normal copper metabolism
Dietary intake = 4mg / day, 2mg absorbed, 2 mg excreted in bile
Absorbed from the gut bound to albumin
Bound to caeruloplasmin and alpha2-globulin in the circulation
Transported by transmembrane cation ATPase which has 6 copper binding units
Each copper binding site is formed from 2 cysteine residues linked by two other amino acids
There are 3 ATPases on the extracellular domain of the protein
Transport of Cu:
ATP7A ATP7B
Gut enterocyte Liver blood
Blood brain Liver bile
Blood tissues Mammary glands milk
Placenta foetus
1. Hence, normally copper enter the blood from gut via ATP7A
2. At the liver it is released from albumin and enters the liver sinusoid through CTR1
3. In hepatocyte it binds intracellular caeruloplasmin and is transported to the golgi, where it
accumulates in vesicles budded off from the golgi
4. Then binds caeruloplasmin to allow transport bile canaliculi
5. Secreted in bile
Wilson’s disease
Autosomal recessive; carrier frequency = 1/90 hence MZ frequency 1/30 000, but not all
phenotypic
Mutation on 13q which codes for transmembrane cation channel ATPase transporter
(ATP7B).
There are >250 mutations identified, mostly in the ATPase domains
Many sufferers will have a different mutation on each chromosome
Polymorphisms vary geographically e.g. 5’UTR deletion in 60% of Sardinians / His1069Gln in
70% polish and 30% greek sufferers
Mutation on ATP7B causes copper to enter from the gut and enter hepatocytes but not be
able to be secreted into bile accumulation in hepatocytes
Toxic effects of Cu in hepatocytes cause lysis release of free Cu in serum
As ATP7A is still functional this free Cu in serum can accumulate in the brain and eye
In response to lack of excretion, 1mg/day is excreted by the kidney (though this causes
toxicity renal failure)
So 1mg accumulates per day
N.B. Copper can also accumulate in cholestatic liver disease where the flow of bile is blocked
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
= a classic example of endogenous drug toxicity. Copper (found in nuts and mushrooms) = a trace element required for essential enzyme function. Dietary intake = 4mg / day, 2mg absorbed, 2 mg excreted in bile. Bound to caeruloplasmin and alpha2-globulin in the circulation. Transported by transmembrane cation atpase which has 6 copper binding units. Each copper binding site is formed from 2 cysteine residues linked by two other amino acids. There are 3 atpases on the extracellular domain of the protein. Mammary glands milk: hence, normally copper enter the blood from gut via atp7a, at the liver it is released from albumin and enters the liver sinusoid through ctr1. In hepatocyte it binds intracellular caeruloplasmin and is transported to the golgi, where it accumulates in vesicles budded off from the golgi: then binds caeruloplasmin to allow transport bile canaliculi, secreted in bile. Autosomal recessive; carrier frequency = 1/90 hence mz frequency 1/30 000, but not all phenotypic.
