Biliary copper excretion in the neonatal rat: Role of glutathione and metallothionein

Abstract

Metallothionein (MT) and glutathione (GSH) have been implicated as two major copper-binding agents involved in the hepatobiliary copper metabolism in the adult rat. This study was designed to explore their potential role in facilitating copper export from the copper-laden hepatocyte of the newborn rat. Biliary and hepatic copper, GSH, and immunoreactive MT-I concentrations were measured in Sprague-Dawley rats at 1, 2, 3, 4, and 8 weeks of age. Bile was collected by duct cannulation for 90 minutes before the rats were killed. Liver was removed, weighed, and freeze-dried. The bile flow rate (BFR) doubled and the liver weight increased 14-fold during maturation. Hepatic and biliary copper and MT-I concentrations were significantly higher in the suckling than in the weanling. The total biliary output of copper per 24 hours was low at 1 week and increased significantly by 8 weeks of age. MT-I-bound copper represented a maximum of only 3.4% of biliary copper at 1 week and 0.5% at 8 weeks. GSH was not detected in bile until 2 weeks and then increased 15-fold by 8 weeks, while hepatic GSH levels remained unchanged. Therefore, GSH levels did not correlate with the high biliary copper concentration at week 1, although there was a close correlation between the total daily biliary excretion of copper and GSH at 2 weeks and beyond. We conclude that the net biliary copper excretion per day is relatively low in the first week of life and is independent of MT and GSH secretion. It increases significantly once GSH is available in bile.(ABSTRACT TRUNCATED AT 250 WORDS)

ATP7B Copper-Regulated Traffic and Association With the Tight Junctions: Copper Excretion Into the Bile

“…poorly incorporated into ceruloplasmin at the Golgi when the translocase is defective 11 , excretion is diminished leading to the metal sequestration in lysosomes 12 , and typically a copper pan-toxicosis ensues severely damaging the liver and central nervous system. While the Wilson disease is Mendelianlinked to ATP7B, the ethiopathology of three hepatic copper toxicosis described in humans that are not Mendelian-linked to ATP7B remains unknown [13][14][15] , pointing to our limited knowledge of the mechanisms that function in copper disposal in the liver.…”

Copper

“…This saturation mechanism is not "fool-proof" however, and with larger amounts of copper in the diet the absolute amounts of absorbed Cu will be higher then when Cu intake is low. Metal ions are also sequestrated into lysosomes, especially under conditions of copper overload (Mohan et al 1995). A portion of the absorbed Cu is lost during the turnover of the intestinal cells and is subsequently lost in the feces.…”