R.U. Habriev, G.I. Kaletin, A.I. Brusilovskiy, N.I. Kaletina

Metabolism, transport, deposition and elimination of metal ions are attributed to their ability to form complexes with endogenous and exogenous ligands. Intensity and specific features of the response of the organism to the imbalance of elements (metals) or ligands (L) are individual and genetically caused . Еlementogram is a dynamic indicator of metal-ligand homeostasis (MLH).It can be used for prenosological diagnostics and for the subsequent planning of patient-specific treatment. New compounds of Zn, Co, Cu, Ni, Fe, Mn built on the principle of coordination structures with ligands (antimicrobial agents) such as 5-nitroimidazole (5-NIMZ) derivatives, long-short-acting 5-nitrofuran derivatives, sulfonamides derivatives and others were synthesized in Russia and are protected by Russian patent law. Composition and structure of these complexes were determined using the methods of IR- and UV- spectroscopy, NMR, AAS, ICP-MS and other. X-ray structural analysis of complexes revealed that their structures resemble the active centers of a number of enzymes. For example, the site of specificity of Zn complex with metronidazol (МN - Zn) is identical to the active center of carbonic anhydrase C in: coordination bond of Zn with three MN molecules via N3 of the imidazole ring, tetrahedral structure of the complex, the water molecule in the inner sphere of the complex. Binding sites of metal ions with different ligands can «trap» superoxide anion radicals; suppress their formation by direct inhibition of the enzymes involved in the process of enzymatic production of reactive oxygen species; incorporate into hydrophobic core of membranes and reduce the fluidity of membrane lipids; comprise steric barriers for the transport of free radicals, i.e. reduce the rate of membrane peroxidation process. Tetrahedral structure of the complexes is complementary to the conformation of carbon backbone chain of fatty acids of phospholipids. Molecules of these compounds present a system of sites that provides multifunctional mechanism of their antioxidant action. The complexes are «recognizable» by the cell and can demonstrate enzyme-imitating ability by delivering activated ions of metals, inducing the shift of electron density at the reactive part of substrate, i.e. by facilitating the process of dynamical recognition, or induction of correspondence. Bank of pharmacological properties of the complexes increased significantly compared with the ligands and their mechanical mixtures with metal salts. The complexes of МN with metals demonstrate a high antiprotozoid activity against Tr.vaginalis resistant to МN. Complex restores of MLH when it is violated, the factors of different nature; they act at low and ultra-low concentrations; they promote the development of compensatory adaptive reactions in liver, spleen and kidneys. For example, the use of complexes МN - Zn и MN-Cu in the form of hydrophilic ointments and creams in the full-thickness skin wound model results in a significantly reduced change in the levels of Cu, Zn, Ni, Fe, Mn, Cr, Mo (compared to MN and metal salts) and in their ratios in blood and hair of the experimental animals. In addition, the histologic examination of the wound surface demonstrated the following effects: thickening of the wound edge epidermis due to the increased amount of small basal cells; a 1.3 to 1.5-fold increase in concentration of nucleic acids in the cytoplasm of basal and stratum spinosum layers; increased rate of epithelization that occurred on day 7 as compared with day 10 in other series; a 3-fold increase in collagen fiber volume and in fibroblasts - number in granulation tissue compared to analogous values in other series. The information of elements analysis of biological objects may be used for different aims, for example: before clinical researches safety of potential drags; the assess of well-being in chain «person-environment - drags »; the researches of new drags generation of personals medicine ( originals complex combinations of metals and drags). So, persons with a high level of arsenic in the hair and some disorder of the elements balance (strong decline in the ratio of elements Si/Hg, Zn/Hg, Se/Hg, P/Hg, Ni/Hg и Nb/Hg against 2-5 times reduction of ratio of Mo/Co, Nb/Ni, Fe/Co, Se/Mo, Cu/Fe, Zn/Cd in comparison with control level) were refered to a group with a high risc for onset of oncology disease. Method of ICP-MS were obtained by the primary (or preliminary) stressor and specific elementogrammy various of biological objects, with 10 diseases. Metabonomics is one of the new analytic technologies that facilitates the detection of various metabolic changes in biological fluids during intoxication. Biomarker of intoxication, for example, is changing the content of ferritin, which is related to a violation of deposits and metabolism Fe. With the help of tandem capillary electrophoresis technology - ICP-MS (KEF-ICP-MS) were divided metallothionein and ferritin, as well as the levels of Cd, Cu, Zn and Fe in the blood of experimental animals (rats) after 5 sessions of intensive external beam radiotherapy. Our experiment showed no change in concentration of Ferritin. However we were able to observe changes in gamma-resonance (GR) - spectrum of Ferritin which signifies change in electronic state of Iron atoms. These changes were dependant on the levels of Cd in the blood samples. Most probably these changes in atoms Fe arose from the presence of ions Cd in the globules of Ferritin rather than from the change in ligand content or the charge of atoms Fe. The advantage of gamma-resonance spectroscopy GRS) is to allow simultaneous detection of atom structure and mobility. Functional activity of protein (Ferritin is this instance) is determined by mobility of its fractions which is caused by conformational transformations. Application of immunohistochemical methods and new types of color cells (AB * HE) identified the link between the activity of genes and common phenotypes, together with methods of GRS and ICP-MS allowed us to estimate the effect of complex compounds MN with the salts Co, Zn, Ni, Cu and sulfates of these metals on the regulation of apoptosis.