The ontogeny of liver copper metabolism in the guinea pig: clues to the etiology of Wilson's disease.
The normal human neonate has a copper profile indistinguishable from Wilson's disease, and we have previously postulated that this disease is caused by genetic failure to switch from the fetal to adult mode of copper metabolism. This study validates the developing guinea pig as a suitable animal in which to study copper ontogeny. At birth, liver copper concentrations are 7 times higher than in adults and serum copper and ceruloplasmin are 27 and 21% of adult values, respectively. A 53% fall in liver copper occurs in the 4 days after birth. This is associated with a marked increase in bile copper output, which does not parallel increasing bile flow. Liver copper falls, and serum copper and ceruloplasmin increase to near adult levels in the 30 days after birth. Until the sixtieth day of gestation, liver copper was significantly increased in copper-stressed littermates, although paradoxically at birth, concentrations were significantly lower. In copper-stressed fetal animals, bile copper output increased markedly before birth. Metallothionein was the dominant copper-binding protein in the fetal liver but a minor component in the adult. Superoxide dismutase activity only developed after birth. We conclude that the postnatal switch from the fetal to adult mode of copper metabolism involves activation of biliary excretion and ceruloplasmin export as well as changes in the association of copper with hepatic copper proteins. Similarities between the fetus and Wilson's disease suggest that this disease is caused by failure of this postnatal adaptation process.
Srai
S K
SK
Burroughs
A K
AK
Wood
B
B
Epstein
O
O
D000375:Aging; D000818:Animals; D001646:Bile / Q000378:metabolism; D002570:Ceruloplasmin / Q000378:metabolism; D003300:Copper / Q000378:metabolism*; D005260:Female; D005333:Fetus / Q000378:metabolism; D006168:Guinea Pigs; D006527:Hepatolenticular Degeneration / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008668:Metallothionein / Q000378:metabolism; D011247:Pregnancy; D013054:Spectrophotometry, Atomic; D013482:Superoxide Dismutase / Q000378:metabolism
D003300:Copper; D008668:Metallothionein; D013482:Superoxide Dismutase; D002570:Ceruloplasmin