The Biochemistry of Titanium

Despite being one of the most abundant metals, titanium, together with aluminum, is apparently not used by organisms. Both elements do not satisfy the rigorous requirements for essentiality in studies to date. Titanium inhibits numerous hydrolytic enzymes, and as titanate can be stimulatory, but there is no evidence that it is bioessential.5 At least two explanations can be suggested to account for these findings.2

One suggestion is that despite its abundance, titanium may not be sufficiently available for use by organisms, because it is extensively hydrolyzed in its usual oxidation state Ti(IV) to form insoluble hydroxides in neutral aqueous media. This argument would be consistent with the general observation that the elements' abundance in living systems today generally reflects their relative amounts in the sea, where life possibly started. However, the same argument could be made with regard to Fe(III), and iron is essential. Therefore, if organisms had found titanium to be useful, they could well have developed mechanisms to extract it, just as they did with iron. The second possibility therefore is that titanium simply has no useful role in organisms and hence is not utilized.

Because titanium metal has uniquely useful properties in modern technology, about 5 x 106 tons of titanium ores are manufactured worldwide per year.6 The question arises as to whether this fact gives rise to toxicity problems due to the accumulation of titanium in the biosphere, for example by blocking essential functional groups of biomolecules or by replacing essential metal ions in biomolecules by titanium. The answer is most probably no.

Titanium is generally considered as one of the most biocompatible and corrosion-resistant metals available for clinical applications. Since the first publication on the orthopedic application of titanium metal in 1951, research activity and clinical experience resulted in new developments in the manufacturing and use of this metal and a variety of its alloys.7 Medical application of titanium and its alloys include hip or knee endoprotheses, heart pacemakers, central venous ports connected to a catheter for deliverance of long-term chemotherapy, and calcium phosphate-coated titanium dental implants. Three classes of composites based on titanium materials offer interesting properties:8 (i) Ti/porous composites have special mechanical properties for isoelastic implants, (ii) Ti/ceramic composites show improved osseointegration of the implants and (iii) the special physical properties of Ti/ceramic composites make them suitable for heart pacemaker leads. In addition to the use of titanium in medical devices, titanium dioxide is a UV-reflecting component of many sunscreen agents, has replaced lead in paints, and is present in many foods as a whitening pigment. Two recent papers deal with the potential mutagenic risk of the exposure to titanium dioxide as well as to wear particles of joint implants.

No significant trends for exposure risk associations for cancer were observed.9,10

Not only bio-compatibility of titanium compounds, but even bio-activity of titanium-containing composites has been claimed. For example, a K2Ti6O13 bio-ceramic coating on the surface of a Ti/Al/Zr/Sn/Nb alloy has recently been tested in a simulated body liquid.11 Rough surfaces and small holes on the Ti-alloy coating provided sites for stimulated bone attachment by encouraging the active formation of a Ca—P layer with a ratio of calcium and phosphorus appropriate to human bone.

In discussing the potential toxicity of titanium anti-cancer drugs described in the following sections, it must be taken into account that, in contrast to TiO2 and titanium-alloys, these titanium drugs probably contain easily exchangeable ligands. In addition, the drugs usually are applied parenterally, e.g. iv injection, and therefore are immediately available for biochemical reactions.

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