Abstract
Abstract
Cadmium has no known function in higher organisms, which evolved in an essentially cadmium‐free environment until the last several hundred years of industrial activity. Thus, cadmium's interactions with biological molecules are not selected by evolution but are determined fortuitously by its inorganic chemistry. Under physiological conditions, cadmium exists exclusively in the Cd
2+
ionic state, and its biomolecular interactions are dominated by two, at first sight contradictory, principles. On the one hand, Cd
2+
is a Group 12 “soft” ion, and as such shows preferential interaction with thiols and other soft ligands. On the other hand, its ionic radius is a close match to the “hard” ion Ca
2+
, and it fits by mimicry into many oxygen‐rich Ca
2+
‐binding sites. Both aspects of Cd
2+
chemistry are covered in this article. General effects of Cd
2+
on cellular Ca
2+
levels have implications for multiple signaling pathways. Interactions of Cd
2+
with Ca
2+
binding sites in specific proteins are also of consequence. Together, these aspects of Cd
2+
biology have consequences for cell survival and proliferation, and for mechanisms of cell death. A special class of Cd
2+
‐sequestering proteins, the thiol‐rich metallothioneins, buffer cytosolic levels of Cd
2+
, and also serve as a strong link between it and the essential Zn
2+
ion; displacement of Zn
2+
from important binding sites, not only in metallothioneins and related proteins, but also in Zn
2+
‐binding loops (“zinc fingers”) in various transcription factors is another important theme in the biological chemistry (and toxicology) of Cd
2+
. Cellular thiols are involved as both protective antioxidants against reactive oxygen species and as signaling sensors of cellular redox status. Cadmium interacts with many of these sensing and defensive pathways. The antioxidant glutathione is a crucial player in redox biology, and Cd
2+
exerts some of its biological effects by influencing levels of protein glutathione adducts. It also interacts with proteins involved in sensing cellular oxygen levels, such as Nrf2 and the hypoxia‐inducible factor 1. The ability of Cd
2+
to act both as a Ca
2+
mimic and a thiol group poison also allows it to interact with a wide range of other proteins. In addition to proteins involved in signaling and cell death pathways, these include interactions with cell membrane transport proteins, DNA repair enzymes, and the structural components of the cytoskeleton, all with profound biological consequences. Cadmium (as the Cd
2+
ion) has truly pleiotropic, and generally adverse, effects on cells that are understood by the inorganic chemistry of its interactions with biological ligands.