Iron and copper interactions in humans: models and mechanisms.

Fe and Cu are both essential trace elements but they can be toxic in excess and therefore need to be tightly regulated. In the body, trace metals rarely act independently from each other or from other nutrients and compounds in the diet. The aim of the present study was to investigate several aspects of Fe and Cu metabolism and their interactions. The work involved the use of models in vivo and in vitro. In an initial human trial, the physiological variation in Fe status during pregnancy was used as a tool to examine how Fe and ceruloplasmin were inter-related in humans. Fifty three pregnant women, aged from 19 to 39 years (29.8 ± 1.08 years), referred for antenatal care were recruited at the Aberdeen antenatal clinic (Aberdeen Maternity Hospital, U.K.). Venous blood samples were taken at 34 weeks of gestation and a range of Cu and Fe indicators were measured. It is well established that iron and ceruloplasmin interact in animals and models in vitro. However, Fe mediated regulation of ceruloplasmin has never been investigated in humans. In the population studied, an inverse linear relationship (r=0.37, p<0.05, n=41) between Fe status and ceruloplasmin was demonstrated. In addition to these observations, soluble transferrin receptor (sTfR) concentration showed a significant increase with parity. While the study provided interesting physiological observations, a direct effect of Fe on Cu metabolism could not be tested. In an effort to determine the mechanisms behind this interaction a cell model was developed and evaluated in Chapter 4. Using in vitro cell culture (HepG2) facilitated the study of both Fe and Cu metabolism over a wide range of concentrations and treatments. The effect of Fe levels on Cu status has been studied extensively over the past 30 years. Typically, radionucleotides were used in experiments with their associated problems. In Chapter 4, an alternative method to study Cu uptake in cells using stable Cu isotope ICP-MS (Inductively Coupled Plasma Mass Spectrometry) in HepG2 cells was developed and evaluated. This technique is based on the measurement of the isotopic ratio by ICP/MS. Cu uptake was temperature and time dependent, with kinetic parameters (Vmax 32.8 ± 3.34 fmol.upsilon g DNA-1.min-1 , Km of 2.59 ± 0.79 upsilon M) in the range of those found in the current literature. The method developed was suitable for studying Cu uptake in HepG2 cells but was time consuming and not practically easy to perform routinely, therefore the effect of Cu on Fe levels and the subsequent consequences for Fe regulated proteins were investigated. Cu supplementation decreased intracellular Fe levels without affecting protein and mRNA levels of IRE/IRP regulated proteins. In contrast, Cu loading induced both transferrin and ceruloplasmin production and secretion. Messenger RNA levels were not changed. While it is well established that trace elements regulate the transcription of various proteins, this thesis provides evidence that Cu may enhance the translation of specific gene products involved in Fe metabolism. This could be a novel mechanism by which Cu regulates protein levels.

Grantor dc:publisher.institution

Robert Gordon University

Year dc:date.issued

2002

Author dc:creator

• Fosset, Cédric

Advisor dc:contributor.advisor

• B.A. McGaw and H.J. McArdle

• Iron and copper interactions
• Human
• Metabolism
• In vivo
• In vitro
• Ceruloplasmin
• Soluble transferrin receptor

Language dc:language

en

Identifier

oai:rgu-repository.worktribe.com:2807387
https://doi.org/10.48526/rgu-wt-2807387

OAI identifier oai:identifier

oai:rgu-repository.worktribe.com:2807387