Novel biological markers for diagnosis and prognosis of poisoning with organophosphates, with special reference to acylpeptide hydrolase

Finding specific markers for changes in the biological systems after taking drugs or the consequences of exposure to toxic chemicals in the environment are increasingly important. Herein, the available biomarkers for documenting the interaction of organophosphorus compounds (neuroparalytic agents, pesticides, and drug preparations) with the biological systems as inhibition of cholinesterase group enzymes (AChE and BuChE) are reviewed. The advantages in the study of the activity of acylpeptide hydrolase in the blood for prevention and diagnosis of the organism changes after interaction with an organophosphorus compound are highlighted

Immune system - drug metabolism interactions: Toxicological insight

From many years the inflammation is considered as one important determinant of susceptibility to intoxication by xenobiotic exposure. Inflammation and vaccination in most cases are connected with immune system stimulation and release of cytokines, adipokines, reactive oxygen species, nitric oxide, proteases, and lipid metabolites. That was accompanied by different extend of down-regulation of the main xenobiotic/drug metabolizing enzyme system cytochrome P450 (CYP) both in the liver and the adipose tissue. We need more knowledge of possible changes in the pharmacokinetics respectively in effectiveness and side effects of drugs used in chronically ill patients in case of occurrence of acute viral or bacterial infection in them or after the application of different vaccines. This would contribute significantly to the optimization of personal drug therapy avoiding toxicity or lack of effectiveness. Here we tried to summarize some of the main experimental and clinical data of altered drug metabolizing enzyme system in the case of changes in the immune system due to inflammation or vaccination

Manipulating Cytochrome P450 Enzymes: New Perspectives for Cancer Treatment

Increasing drug efficiency and reducing drug overall toxicity are two of the main goals of today`s drug chemotherapy of cancer. In general this could be achieved by searching new ways for selective active drug accumulation in cancer cells by manipulating local drug metabolism or delivery. In this short review, on the basis of the main directions described by McFadyen et al. (Mol Cancer Ther 2004; 3(3): 363-371), new data is reported for localization and expression of cytochrome P450 enzymes in human tumors, development of cytochrome P450-based and gene-directed enzyme activated prodrugs, antisense-based P450 and immune-based therapy, cytochrome P450 polymorphism in development of anticancer drugs. New discoveries of molecular biology of cancer give us hope for more successful development of modern cancer chemotherapy. Biomed Rev 2017; 28: 120-124.Keywords: cytochrome P450 isoforms, cancer cells, drug metabolism, drug deliver

Adipose tissue: a master in toxicology

Conventional wisdom in the pathogenesis of obesity and related cardiometabolic, malignant and neurodegenerative diseases focuses mainly on genetic predisposition and lifestyle (high caloric foods, sedentary lifestyle, smoking). The human genome project's big promise was that it could improve our understanding of the pathogenesis and therapy of diseases. However, the genes have been found to account for only about 10% of diseases, and the remaining causes appear to be from environmental exposures, hence the exposure science emerges. Note that molecular epidemiology and toxicology may be essential partners of exposure science. Indeed, Homo sapiens recens is exposed to an overwhelming number of chemical contaminants circulating every day in the air, water, food, and general environment. The body is a well-equipped entity with capabilities to excrete water-soluble pollutants, but not as well-equipped to excrete some of the lipid-soluble xenobiotics. In the late 1990's, according to the European Environmental Agency more than 100 000 chemical compounds were registered in the European Catalogue of Commercialized Chemical Substances. Here we present data that adipose tissue may be an important participant in the environmental molecular toxicology. The discovery of adipocyte-secreted leptin in 1994 was a paradigm shift event in the study of adipose tissue. It was applauded by scientific community and thus triggered a new direction in the evaluation of endocrine function of adipose tissue, that is, adipoendocrinology. This is why the today's adipose tissue is viewed not merely as a lipid storage, but also as a dynamic secretory - endocrine and paracrine - organ, synthesizing, storing, and releasing a dazzling number of signaling proteins collectively termed adipokines. Numerous evidence demonstrates that the exposure to persistent organic pollutants (POP) may contribute to the pathogenesis of obesity and its related diseases. Noteworthy, these pollutants accumulate mainly in the adipose tissue. And xenobiotic-metabolizing cytochromes p450 (CYP ) are expressed in adipose tissue, where CYP 1A1 and CYP 1B1 can bioactivate carcinogenic polycyclic aromatic hydrocarbons and xenoestrogens. Altogether, the present review highlights an adipocentric approach in molecular toxicology. It is conceptualized as adipotoxicology, that is, the study of accumulation, metabolism, and release of xenobiotics in adipose tissue in health and disease. In effect, the adipose tissue may be a new bridge between environment and health - let us call it a master in toxicology.Adipobiology 2012; 4: 59-66

Adipotoxicology of obesity and related diseases

The human genome project's big promise was that it could improve our understanding of the pathogenesis and therapy of diseases. However, the genes have been found to account for only about 10% of diseases, and the remaining causes appear to be from environmental exposures, hence the exposure science (exposome concept) emerges. Indeed, Homo sapiens is exposed to an overwhelming number of chemical contaminants circulating every day in the air, water, food, and general environment. The body is a well-equipped entity with capabilities to excrete water-soluble pollutants, but not as well-equipped to excrete some of the lipid-soluble xenobiotics. Here we present data that adipose tissue may be an important participant in the environmental molecular toxicology. Numerous evidence demonstrates that the exposure to persistent organic pollutants may contribute to the pathogenesis of obesity and its related diseases. Noteworthy, these pollutants accumulate mainly in the adipose tissue. And xenobiotic-metabolizing cytochromes p450 (CYP) are expressed in adipose tissue, where CYP1A1 and CYP1B1 can bioactivate carcinogenic polycyclic aromatic hydrocarbons and xenoestrogens. Altogether, the present review highlights an adipocentric approach in molecular toxicology. It is conceptualized as adipotoxicology, that is, the study of accumulation, metabolism, and release of xenobiotics in adipose tissue in health and disease.Biomedical Reviews 2012; 23: 53-60

RME-based pharmacology: The inhibition of viral entry as therapeutic perspective in viral diseases including AIDS. Hypothesis updated and enlarged

In 1990, one of us (GNC) for the first time reported a hypothesis of receptor-mediated endocytosis (RME)-based pharmacology relevant to the possible antiviral therapy including in acquired immunodeficiency syndrome (AIDS). Then, RME using clathrin-coated pits/vesicles was the best-characterized endocytic pathway. Since then now, intensive research on the mechanisms of both RME and receptor-mediated virus-cell fusion (receptor-mediated fusion - RMF) helped to expand the list of chemical compounds with potential clinical application as antiviral agents, the so-called entry inhibitors, e.g. (i) inhibitors of clathrin-, dynamin-2-, caveolin- and/or lipid rafts-dependent RME, and (ii) inhibitors of RMF. Accordingly, in the present Dance Round we update and enlarge our hypothesis of RME-based antiviral pharmacology

The fibrous cap: a promising target in the pharmacotherapy of atherosclerosis

Recent advances have shed light on the relationship between smooth muscle cell (SMC) phenotypic modulation, resolution of inflammation and atherosclerotic plaque stability. The thick fibrous cap covering the lipid core of plaques is composed of bundles of SMC and collagen fibers and few macrophages and lymphocytes, all of which make the plaque resistant to rupture. The thin fibrous cap contains many macrophages and lymphocytes, few SMC and less collagen fibers, all of which may weaken the cap, leaving the plaque vulnerable to rupture. In the present Dance Round, we, at a pharmacotherapeutic level, address the possibility of how the control over the activity of the essential cellular components of the plaque, particularly its fibrous cap, could be implicated in plaque stabilization, focusing on (i) the modulation of SMC from contractile to secretory (fibrogenic) phenotype, (ii) the control on plaque inflammation-resolution processes, and (iii) the reduction of plaque lipid content. Further studies on both unstable plaque and aortic aneurysm, which share a similar, matrix-based vulnerability, may bring new insights for pharmacotherapy of vascular injuries

The mast cell: Another master in adipoimmunology

Recently, a large number of studies focus on (i) adipose tissue endocrine and paracrine function, and (ii) adipose-immune interactions herein referred to as adipoimmunology. In effect, a wide range of signaling proteins, dubbed adipokines, was identified as endocrine and paracrine secretory products of adipocytes and associated stromal vascular cells, including macrophages, lymphocytes and mast cells, the latter being less evaluated as compare to the formers. During obesity immune cells migrate into adipose tissue and inflame it by the secretion of a large amount of adipokines and thus trigger the development of so-called low grade inflammation-related diseases. Based on Steve Galli`s concept of mast cell as master cells in many biological and pathological processes (New Engl J Meet 1993; 328:257-265), here we highlight recent studies on the significance of adipose mast cells in the pathogenesis and therapy of cardiometabolic diseases (atherosclerosis, obesity, type 2 diabetes mellitus, metabolic syndrome) and breast cancer. Knowledge of the master work of these cells may provide a background for mast cell-targeted pharmacology for low grade inflammation-related diseases.Adipobiology 2015; 7: 15-19Key words: adipose tissue, adipokines, atherosclerosis, breast cancer, inflammation, mast cells, obesit

Xanthates: Metabolism by Flavoprotein-Containing Monooxygenases and Antimycobacterial Activity.

Ethionamide (ETH) plays a central role in the treatment of tuberculosis in patients resistant to the first-line drugs. The ETH, thioamide, and thiourea class of antituberculosis agents are prodrugs that are oxidatively converted to their active S-oxides by the mycobacterial flavin-dependent monooxygenase (EtaA) of Mycobacterium tuberculosis, thus initiating the chain of reactions that result in inhibition of mycolic acid biosynthesis and cell lysis. As part of a search for new lead candidates, we report here that several xanthates are oxidized by purified EtaA to S-oxide metabolites (perxanthates), which are implicated in the antimycobacterial activity of these compounds. This process, which is analogous to that responsible for activation of ETH, is also catalyzed by human flavoprotein monooxygenase 3. EtaA was not inhibited in a time-dependent manner during the reaction. Xanthates with longer alkyl chains were oxidized more efficiently. EtaA oxidized octyl-xanthate (Km = 5 µM; Vmax = 1.023 nmolP/min; kcat = 5.2 molP/min/molE) more efficiently than ETH (194 µM; 1.46 nmolP/min; 7.73 nmolP/min/molE, respectively). Furthermore, the in vitro antimycobacterial activity of four xanthates against M. tuberculosis H37Hv was higher (minimum inhibitory concentration of around 1 µM) than that of ETH (12 µM)