What is the role of metallothionein in zinc and copper pharmacokinetics?

Metallothionein's Central Role in Zinc and Copper Pharmacokinetics

Metallothionein (MT) is a cysteine-rich intracellular protein that serves as the primary regulator of zinc and copper absorption, distribution, and homeostasis by preferentially binding these metals and controlling their bioavailability at the enterocyte and hepatocyte level. 1

Mechanism of Action in the Gastrointestinal Tract

Zinc induces enterocyte metallothionein synthesis, which then preferentially binds copper over zinc due to its higher affinity for copper, effectively blocking copper absorption from the intestinal lumen. 1 This mechanism is exploited therapeutically in Wilson's disease treatment, where zinc supplementation (typically 900-2700 mg/day in divided doses) induces MT to prevent dietary copper absorption. 1

• Once copper binds to enterocyte MT, it remains trapped within the intestinal cell and is lost into fecal contents as enterocytes undergo normal turnover (approximately every 2-6 days). 1, 2
• This copper-blocking effect persists for 2-6 days as long as zinc intake continues, explaining why temporal separation of zinc and copper supplements by at least 5-6 hours is necessary to prevent competitive inhibition. 2
• Copper entering the GI tract from endogenous sources (saliva, gastric secretions) is also trapped by zinc-induced MT, creating a negative copper balance that can remove stored body copper over time. 1

Hepatocellular Metallothionein Function

Beyond the intestine, zinc may induce hepatocellular MT levels, which serves a protective function by binding excess toxic copper and preventing hepatocellular damage. 1 This dual mechanism—blocking absorption at the gut level and sequestering copper at the hepatocyte level—makes MT central to copper detoxification pathways. 3, 4

Tissue-Specific Regulation and Expression Patterns

MT gene expression responds differently across tissues based on dietary zinc and copper intake:

• Kidney MT is highly responsive to dietary zinc, with mRNA levels increasing 4-5 fold (from 4 to 29 molecules per cell) as zinc intake rises from deficient to supplemental levels. 5
• Intestinal MT shows the most dramatic response when low copper intake coincides with high zinc intake, with mRNA levels increasing sevenfold compared to other dietary combinations. 5
• Liver and brain MT are relatively unresponsive to the dietary zinc and copper variations that profoundly affect kidney and intestinal MT expression. 5
• Maximum MT expression occurs approximately 18 hours after zinc administration, reflecting the protein's half-life and optimal induction timing. 6

Pharmacokinetic Implications for Supplementation

The MT system creates critical pharmacokinetic interactions that must be managed clinically:

• The recommended zinc-to-copper ratio of 8:1 to 15:1 prevents zinc-induced copper deficiency by balancing MT induction with adequate copper availability. 7, 2, 8
• Zinc doses above 15-25 mg daily require copper monitoring because MT induction can deplete copper stores over prolonged periods, manifesting as anemia, leukopenia, thrombocytopenia, and myeloneuropathy. 7, 8
• All zinc salts (sulfate, acetate, gluconate, orotate) induce MT identically and block copper absorption equally, though tolerability differs among formulations. 8

Protein Stability and Metal-Dependent Degradation

MT degradation rate varies based on which metal species is bound:

• MT is fairly rapidly degraded when zinc is the primary bound metal. 3
• Degradation slows considerably when cadmium or copper are also bound, leading to accumulation of these metals in tissues. 3
• This differential stability explains copper accumulation in Menkes' and Wilson's diseases, where altered MT turnover contributes to pathological metal distribution. 3

Clinical Monitoring Based on MT Dynamics

Understanding MT pharmacokinetics informs monitoring strategies:

• Urinary copper excretion on zinc therapy should be <75 μg per 24 hours, reflecting effective MT-mediated copper blockade. 1
• When using chelators like trientine, urinary copper should be 200-500 μg per 24 hours (measured after 2 days off therapy), indicating mobilization rather than MT-mediated trapping. 1
• Serum copper <8 μmol/L indicates definite deficiency requiring immediate zinc cessation and copper supplementation at 4-8 mg daily. 8
• Recheck zinc and copper levels every 3-6 months when supplementing either mineral to ensure MT induction hasn't disrupted the balance. 7, 2

Optimal Dosing Timing to Manage MT Effects

• Take zinc at least 30 minutes before meals for optimal absorption, as food interferes with zinc uptake but doesn't eliminate the copper-blocking effect. 7, 2
• Separate zinc and copper supplements by minimum 5-6 hours to prevent zinc-induced MT from blocking copper absorption at the enterocyte level. 2
• A practical schedule: zinc 30 minutes before breakfast, copper with dinner or bedtime, ensuring adequate temporal separation. 2