Metallothionein

Structure and Binding#

Cysteine content: ~30% of amino acid residues are cysteine, providing abundant thiol (-SH) groups for metal coordination. Two domains: Alpha domain binds 4 divalent metal ions; beta domain binds 3 divalent metal ions. A single MT molecule can bind 7 zinc or cadmium atoms, or 12 copper(I) atoms.

Binding hierarchy (affinity): mercury(II) (Hg2+) > copper (Cu)+ > cadmium(II) (Cd2+) > Zn2+—meaning toxic metals displace zinc when they arrive, which is both protective (sequestering the toxicant) and disruptive (liberating zinc).

Cadmium Detoxification#

When cadmium enters the cell, MT is the primary defense.^{[1]The Effects of Cadmium ToxicityGiuseppe Genchi, Maria Stefania Sinicropi, Graziantonio Lauria et al. · 2020Open reference 1 ↓} cadmium(II) (Cd2+) displaces zinc(II) (Zn2+) from MT due to higher binding affinity. cadmium-MT complex is thermodynamically stable, reducing free cadmium availability.

MT expression is strongly induced by cadmium exposure (positive feedback loop).

However, cadmium-MT is not permanently inactivated—it is filtered at the renal glomerulus and reabsorbed in proximal tubules, where lysosomal degradation (pH 4.5-5.5) releases free cadmium, causing tubular damage. This is the molecular basis of cadmium nephrotoxicity and its connection to Chronic Kidney Disease.

Copper Regulation#

MT binds copper (Cu)(I) with high affinity (12 atoms per molecule). Copper displaces zinc from MT due to higher affinity, creating copper-MT complexes. This copper-zinc (Zn) competition at MT binding sites contributes to the copper/zinc ratio distortion seen across cancer and inflammatory conditions.

Chronic high-dose zinc supplementation induces intestinal MT, which then binds dietary copper, reducing copper absorption—the basis for zinc-induced copper deficiency.

Protection (Initially)#

MT sequesters cadmium, reducing its availability to damage DNA, displace zinc from zinc-finger transcription factors, and activate estrogen receptors as a Metalloestrogen. MT induction is the cell's first-line defense against cadmium (Cd)-mediated genotoxicity.

Enabling Progression (Subsequently)#

Higher MT expression in breast tumors predicts cancer progression and drug resistance. MT sequesters platinum-based chemotherapy drugs (cisplatin, carboplatin) via the same thiol-binding mechanism used for cadmium, reducing drug efficacy.

cadmium (Cd) accumulates preferentially in mammary tissue bound to MT (0.053 ug/g malignant vs 0.02 ug/g normal)—MT enables the accumulation by preventing acute toxicity while permitting chronic estrogenic stimulation.

MT-mediated zinc release under oxidative stress may activate metalloproteinases and other zinc-dependent enzymes that promote invasion and metastasis.