Zinc Toxicity

Induction of zinc toxicity through dietary manipulation is very difficult. In contrast, dietary administration of high levels of the chelator trisodium nitrilotriacetate monohydrate (nta) results in zinc nephrotoxicity. When plasma glomerular ultrafiltrate levels of ntaexceed 20 μm, an increase in plasma and, thus, glomerular ultrafiltrate zinc occurs. In the proximal tubules, zinc is reabsorbed, but nta is not. Nta is not metabolized, and is excreted unchanged in the urine. The increased tubular zinc uptake rapidly leads to persistent changes of osmotic nephrosis, possibly through zinc stabilization of lysosomal membranes. Osmotically-altered proximal convoluted tubules become hypertrophic, and then hyperplastic. Doses sufficient to cause the osmotic type of nephrosis also cause an increase in incidence or severity of lesions of chronic progressive nephropathy in the rat. With lifetime exposure, proliferative sequelae associated with the toxic response are associated with development of rodent renal tubular tumors.

Function
Numerous aspects of cellular metabolism are zinc-dependent. Zinc plays important roles in growth and development, the immune response, neurological function, and reproduction. On the cellular level, the function of zinc can be divided into three categories: (1) catalytic, (2) structural, and (3) regulatory (3).

Catalytic role
Over 300 different enzymes depend on zinc for their ability to catalyze vital chemical reactions. Zinc-dependent enzymes can be found in all known classes of enzymes (4).

Structural role
Zinc plays an important role in the structure of proteins and cell membranes. A finger-like structure, known as a zinc finger motif, stabilizes the structure of a number of proteins. For example, copper provides the catalytic activity for the antioxidant enzyme copper-zinc superoxide dismutase (cuznsod), while zinc plays a critical structural role (5, 6). The structure and function of cell membranes are also affected by zinc. Loss of zinc from biological membranes increases their susceptibility to oxidative damage and impairs their function (7).

Regulatory role
Zinc finger proteins have been found to regulate gene expression by acting as transcription factors (binding to dnaand influencing the transcription of specific genes). Zinc also plays a role in cell signaling and has been found to influence hormone release and nerve impulse transmission. Zinc has been found to play a role in apoptosis (gene-directed cell death), a critical cellular regulatory process with implications for growth and development, as well as a number of chronic diseases (8).

Drug interactions
Concomitant administration of zinc supplements and certain medications, including tetracycline and quinolone antibiotics as well as bisphosphonates, may decrease absorption of both zinc and the medication, potentially reducing drug efficacy (101). Taking zinc supplements and these antibiotics at least two hours apart should prevent this interaction (102). Additionally, the therapeutic use of metal-chelating (binding) agents, such as penicillamine (used to treat copper overload in wilson’s disease) and diethylenetriamine pentaacetate or dtpa (used to treat iron overload), has resulted in severe zinc deficiency. Anticonvulsant drugs, especially sodium valproate, may also precipitate zinc deficiency. Prolonged use of diuretics may increase urinary zinc excretion, resulting in increased loss of zinc. Further, the tuberculosis medication, ethambutol, has metal-chelating properties and has been shown to increase zinc loss in rats (6).

Recommendation
The rda for zinc (8 mg/day for adult women and 11 mg/day for adult men) appears sufficient to prevent deficiency in most individuals, but the lack of sensitive indicators of zinc nutritional status in humans makes it difficult to determine the level of zinc intake most likely to promote optimum health. Following the linus pauling institute recommendation to take a multivitamin/mineral supplement containing 100% of the daily values (dv) of most nutrients will generally provide 15 mg/day of zinc.

Older adults (>50 years)
Although the requirement for zinc is not known to be higher for older adults, their average zinc intake tends to be considerably less than the rda. A reduced capacity to absorb zinc, increased likelihood of disease states that alter zinc utilization, and increased use of drugs that increase zinc excretion may all contribute to an increased risk of mild zinc deficiency in older adults. Because the consequences of mild zinc deficiency, such as impaired immune system function, are particularly relevant to the health of older adults, they should pay particular attention to maintaining adequate zinc intake.