Renal Excretion of Xenobiotics and Estimation of Related PK/TK Parameters and Constants

Abstract

Usanov>Cytochrome P450 (P450) enzymes are widely distributed huge family of heme-thiolate proteins involved in the metabolism of endobiotics and xenobiotics in eukaryotes and prokaryotes and participating in biosynthesis of low molecular weight bioregulators including steroids, vitamins, fatty acids mostly in eukaryotes. The clinical relevance of P450s is in its central role in drug metabolism in human organs and tissues as well as outstanding role that hemeproteins play in biosynthesis of low molecular weight bioregulators such as steroid hormones, bile acids and vitamins. Any abnormalities in functioning of P450 enzymes result in severe diseases or uncontrolled function of organs and tissues. At least several P450 from isozymes, coded by 57 genes found in human genome, are involved in biosynthesis of steroid hormones, bile acids and vitamin D3 catalyzing sequential hydroxylation reactions starting from cholesterol. During hydroxylation reaction, proteins of electron transfer chain form specific complexes to transfer electrons from NAD(P)H to P450 via electron transfer components to activate molecular oxygen. Molecular mechanisms of such specific complex formation and the nature of substrate specificity become evident via computer modeling and understanding of tertiary structure of P450 and their electron transfer partners. In the present report we will summarize our recent results on studies of structure-function mechanisms in P450 dependent catalysis in attempt to understand the nature of highly specific protein-protein interactions and substrate specificity. L.J.2Why adiposity leads to insulin resistance: a biochemist point of view While diabetes has traditionally been thought of as a disorder of carbohydrate metabolism, more recent work indicated that diabetes is also a disease of lipid metabolism. Increased deposition of lipids in tissues other than white adipose leads to insulin resistance and the development of diabetes. Intramuscular lipid accumulation is now evident in a wide array of experimental models, including insulin resistance induced acutely by lipid infusion in both humans and rodents. Genetic forms of obesity such as Zucker rats as well as dietary models of insulin resistance including chronically glucose-infused rats and more recent studies of high-fat fed rats also exhibit increased lipid accumulation. A reduction in intramuscular lipid may also be the mechanism by which the adipose secreted protein leptin improves insulin sensitivity. In contrast to other 'adipokines' such as TNFα and resistin, which are proposed to have detrimental effects on insulin action, leptin can enhance insulin action, and this effect is, at least partly, independent of its effects on food intake and adiposity. More recently, another adipokine of great interest, adiponectin, has been found to have beneficial effects on insulin sensitivity. In fact, the insulin resistance of lipoatrophic mice was completely reversed by combined treatment of adiponectin and leptin at physiological doses. Agnieszka DobrzyńThere have b...