MedicalResearch.com Interview with: Prof. Peter Lay PhD Professor of Inorganic Chemistry School of Chemistry | Faculty of Science Director, Vibrational Spectroscopy Core Facility Research Portfolio The University of Sydney Medical Research: What is the background for this study? What are the main findings? Response: My group has been studying the molecular mechanisms of chromium(VI)-induced cancers and the biochemistry of vanadium over the last three decades. Vanadium drugs have been in clinical trials for their anti-diabetic effects that occur via species with very similar chemistry to chromium(VI).  The more we understood the biochemistry of each, the more we questioned whether the efficacies of anti-diabetic chromium(III) supplements were associated with the generation of carcinogenic chromium(VI) and chromium(V). To test this, we conducted experiments to either provide evidence for our hypothesis or disprove it.  This work commenced some 15 years ago with studies on the changes in the nature of chromium(III) supplements exposed to simulated gastrointestinal juices, as well as in human and animal blood serum over times that mimicked the residence time of the supplements in the human body. We discovered that all supplements were changed to a range of different Cr(III) species in both the GI tract and the blood.^1,2  Common species were observed, but the rates at which they formed were dependent on the nature of the chromium(III) supplement.  Both the supplements themselves and the chromium(III) species that formed in blood serum were partially oxidised to Cr(VI) at concentrations of the oxidant, hydrogen peroxide (a type of bleach), found in the blood of people with type II diabetes.^1,2 One of the clinical features of patients with type II diabetes is increased levels of oxidants, such as hydrogen peroxide, in their blood and cells. These oxidants are associated with many of the side-effects of type II diabetes that are associated with reduced life expectancy. These transformed chromium(III) species bound to blood proteins were more easily oxidised to chromium(VI) than the administered Cr(III) supplements.  The faster a particular chromium(III) supplement reacted with blood proteins to form these easily oxidised chromium(III)-protein species, the more active was the Cr(III) supplement in its anti-diabetic activity in animal and human studies reported by other groups.^1-5  According to many health and regulatory bodies, chromium(III) has minimal or no efficacy in glucose metabolism and no other beneficial effects, such as weight loss or muscle building, in well conducted human and animal trials with non-diabetic subjects. This is consistent with our proposed mechanism of action. It is only under oxidising physiological conditions associated with type II diabetes that chromium(III) can be partially transformed to sufficient concentrations of carcinogenic chromium(VI) to enable significant biological activity.  In a large clinical trial where diabetic patients were treated with high doses of chromium(III) picolinate (one of the least efficacious supplements in animal studies), there was no efficacy in patients with controlled type II diabetes. Only those patients with uncontrolled type II diabetes exhibited improved glucose metabolism.  These patients, who have the highest concentrations of oxidants with the ability to transform chromium(III) to chromium(VI) in blood, are therefore at the greatest risk of developing Cr-induced cancers. Even where efficacy was observed, glucose metabolism was only reduced to the levels in patients with controlled type II diabetes; i.e., no patients exhibited a return to normal glucose metabolism.^4,5 Coupled with all of this information our separate studies showed that chromium(VI) and chromium(V), but not chromium(III), are strong inhibitors of protein tyrosine phosphatase (PTP) enzymes.  The relevance of this is that drugs that inhibit PTPs activate circulating insulin in people with type II diabetes.  That is, it causes insulin to bind more strongly to cells involved in glucose metabolism (such as fat cells) to bring about the cascade of biochemical reactions that import glucose into cells and metabolise it.^1-5 Thus we were able to link all of the animal, human and in vitro studies to show that physiological conditions under which chromium(III) had the highest probability of being transformed to chromium(VI) were also those in which chromium(III) supplements were most active.^1-5 Moreover, we were able to provide a mechanism of activity that required chromium(VI) and chromium(V) to be generated for insulin enhancing activity.^1-5  What remained was to establish whether we could observe Cr(VI) and Cr(V) in cells treated with chromium(III) supplements. This has now been established in our most recent study⁶ that have just been published. Contrary to the press releases of the dietary supplement industry, the published paper was carefully planned to mimic those conditions found in vivo.  The chromium(III) supplement chosen was that which had a chemical structure most closely resembling those generated in blood plasma. Thus we were able to complete the circle in linking our extensive studies on the biochemistry of chromium(III) species generated from chromium(III) supplements in the blood and show that such species were absorbed by the relevant cells and partially oxidised to chromium(VI) and chromium(V). (more…)