Medical applications of Cu, Zn, and S isotope effects

Abstract

This review examines recent applications of stable copper, zinc and sulfur isotopes to medical cases and notably cancer. The distribution of the natural stable isotopes of a particular element among coexisting molecular species varies as a function of the bond strength, the ionic charge, and the coordination, and it also changes with kinetics. Ab initio calculations show that compounds in which a metal binds to oxygen- (sulfate, phosphate, lactate) and nitrogen-bearing moieties (histidine) favor heavy isotopes, whereas bonds with sulfur (cysteine, methionine) favor light isotopes. Oxidized cations (e.g., Cu(ii)) and low coordination numbers are expected to favor heavy isotopes relative to their reduced counterparts (Cu(i)) and high coordination numbers. Here we discuss the first observations of Cu, Zn, and S isotopic variations, three elements closely related along multiple biological pathways, with emphasis on serum samples of healthy volunteers and of cancer patients. It was found that heavy isotopes of Zn and to an even greater extent Cu are enriched in erythrocytes relative to serum, while the difference is small for sulfur. Isotopic variations related to age and sex are relatively small. The Cu/Cu ratio in the serum of patients with colon, breast, and liver cancer is conspicuously low relative to healthy subjects. The characteristic time over which Cu isotopes may change with disease progression (a few weeks) is consistent with both the turnover time of the element and albumin half-life. A parallel effect on sulfur isotopes is detected in a few un-medicated patients. Copper in liver tumor tissue is isotopically heavy. In contrast, Zn in breast cancer tumors is isotopically lighter than in healthy breast tissue. Zn/Zn is very similar in the serum of cancer patients and in controls. Possible reasons for Cu isotope variations may be related to the cytosolic storage of Cu lactate (Warburg effect), release of intracellular copper from cysteine clusters (metallothionein), or the hepatocellular and biosynthetic dysfunction of the liver. We suggest that Cu isotope metallomics will help evaluate the homeostasis of this element during patient treatment, notably by chelates and blockers of Cu trafficking, and understand the many biochemical pathways in which this element is essential.

Cu Isotopic Composition in Surface Environments and in Biological Systems: A Critical Review

“…It is worth mentioning that Cu isotopic signatures have been reported in organs and body fluids of mammals including human beings, though data from human material were very limited for ethical reasons. Oxidized cations such as Cu(II) and low coordination numbers were found to favor heavy isotopes contrast to the reduced product (Cu(I)) and high coordination numbers [16]. For the aquatic animal, such as fish, Komjarova et al [101] determined isotope ratios of Cd and Cu in zebrafish gills and found that Cd uptake was evidently restrained by Cu coexistence, suggesting an interaction between Cu and Cd, yet Cu uptake was not interfered by Cd.…”

“…Cu was translocated by serum albumin, and excess Cu could be stored in metallothione as well [16]. Commonly, Cu was more concentrated in erythrocytes compared with serum.…”

“…Significantly lower δ 65 Cu values were observed in the serum of patients with breast, liver, and colon cancer in contrast to those in samples from healthy individuals [16]. In the blood of hepatocellular carcinoma (HCC) patients, Cu was 63 Cu-enriched by about 0.4‰ compared with that of the control group, and more concentrated Cu was observed in red blood cells and serum of HCC patients [106].…”

“…Hitherto, a large number of studies regarding theoretical, experimental and application data sets of Cu isotope compositions have been published. These studies have largely improved our knowledge on Cu biogeochemical behaviors in biosphere, hydrosphere and lithosphere, and to different extent on Cu isotopic fractionation mechanisms in various geochemical, biological and metabolism processes [15,16,17,18,19,20,21]. …”

Precise determination of the molybdenum isotopic composition of urine by multiple collector inductively coupled plasma mass spectrometry

“…In addition, calcium isotope ratios can identify cancer‐related bone loss and multiple myeloma, while zinc and iron isotope systematics can detect breast cancer and hereditary hemochromatosis, respectively. While the medical application of novel isotope systematics has recently been reviewed, it remains a novel and promising field that requires significantly more research to be completely developed as a complementary analytical approach for medical diagnosis and prognosis.…”