Copper incorporation into ceruloplasmin in rat livers

Terada, Kunihiko; Kawarada, Yoshihiko; Miura, Naoyuki; Yasui, Ouki; Koyama, Kenji; Sugiyama, Toshihiro

doi:10.1016/0925-4439(94)00072-x

Cited by 67 publications

(46 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The expression, localization, and function of ATP7B has been extensively studied and characterized using in vitro models to understand the role of ATP7B in the homeostatic control of Cu and its altered function in disease states. Under low Cu concentrations, ATP7B is localized to the TGN, where its primary function is to transport Cu across the Golgi membrane for incorporation into ceruloplasmin and excretion across the basolateral membrane into the blood (Murata et al, 1995;Terada et al, 1995;Hellman et al, 2002). Results obtained in this study showed that SCRH were able to synthesize and secrete ceruloplasmin in culture.…”

Section: Downloaded Fromsupporting

confidence: 48%

Characterization of Sandwich-Cultured Hepatocytes As an in Vitro Model to Assess the Hepatobiliary Disposition of Copper

Ansede¹,

Wright²,

Claire³

et al. 2009

Drug Metab Dispos

View full text Add to dashboard Cite

ABSTRACT:Sandwich-cultured hepatocytes (SCH) from rats (SCRH), dogs (SCDH), and humans (SCHH) were used as an in vitro model to assess the hepatobiliary disposition of copper (Cu). The expression of Cu transporters, ceruloplasmin synthesis, Cu uptake, and biliary excretion and species differences in drug-induced alterations in Cu disposition were determined in SCH from all species. Western blot analysis verified basolateral Cu uptake transporter 1 (CTR1) and canalicular Cu efflux transporter (ATP7B) expression: enzymelinked immunosorbent assay verified synthesis/secretion of ceruloplasmin (major Cu binding protein found in blood). Endogenous Cu in SCRH, SCDH, and SCHH were 17.2 ؎ 7.00, 490 ؎ 44.8, and 43.5 ؎ 15.8 ng/well, respectively. The hepatobiliary disposition of Cu as measured by uptake (increase in intracellular Cu in comparison to endogenous levels) and biliary excretion (increase in Cu in wash solutions obtained from hepatocytes exposed to calciumfree versus standard buffer) was determined as a function of Cu concentration and incubation time. In general, an increase in Cu concentration or incubation time resulted in an increase in Cu uptake and/or biliary excretion; however, the extent to which they affected Cu disposition was species dependent. 5-(1,1-Dioxido-1,2-thiazinan-2-yl)-N-(4-fluorobenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide (L-000870810) (an anti-HIV compound, the development of which was halted due to an observed Cu-specific toxicity in the liver and kidneys of dogs after long-term exposure) showed no effect on Cu disposition in SCRH; however, it increased the biliary excretion of Cu in SCDH and SCHH. This is the first report to demonstrate the utility of SCH as a model to assess hepatobiliary disposition of Cu in an in vitro system.

show abstract

Section: Downloaded Fromsupporting

confidence: 48%

Characterization of Sandwich-Cultured Hepatocytes As an in Vitro Model to Assess the Hepatobiliary Disposition of Copper

Ansede¹,

Wright²,

Claire³

et al. 2009

Drug Metab Dispos

View full text Add to dashboard Cite

show abstract

“…A possible source of this additional copper is the Cu-protein ceruloplasmin, which is known to be synthesized in the mammary gland and excreted in the milk [18,25]. Normally, it is thought that ceruloplasmin would receive copper in the TGN from ATP7B [26]. However, in the tx mouse this cannot be the case as the mutant Atp7b is unable to transport copper [27].…”

Section: Discussionmentioning

confidence: 99%

Copper transport during lactation in transgenic mice expressing the human ATP7A protein

Llanos

Michalczyk

Freestone

et al. 2008

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

Both copper transporting ATPases, ATP7A and ATP7B, are expressed in mammary epithelial cells but their role in copper delivery to milk has not been clarified. We investigated the role of ATP7A in delivery of copper to milk using transgenic mice that over-express human ATP7A. In mammary gland of transgenic mice, human ATP7A protein was 10-to 20-fold higher than in control mice, and was localized to the basolateral membrane of mammary epithelial cells in lactating mice. The copper concentration in the mammary gland of transgenic dams and stomach contents of transgenic pups was significantly reduced compared to non-transgenic mice. The mRNA levels of endogenous Atp7a, Atp7b, and Ctr1 copper transporters in the mammary gland were not altered by the expression of the ATP7A transgene, and the protein levels of Atp7b and ceruloplasmin were similar in transgenic and non-transgenic mice. These data suggest that ATP7A plays a role in removing excess copper from the mammary epithelial cells rather than supplying copper to milk.

show abstract

“…In addition to its ATP-driven copper transport role at the TGN where copper is incorporated into ceruloplasmin (25,26), the Wilson disease protein is also thought to be involved in the excretion of copper into bile at the canalicular membrane (27). The copper-stimulated trafficking of the transporter between the TGN and the canalicular membrane may involve the N terminus and is not clearly understood (28).…”

Section: The Wilson Disease Coppertransporting P-type Atpasementioning

confidence: 99%