Current Drug Metabolism (v.13, #3)
Editorial: Metal ions in cause, progression, treatment and diagnosis of genetic disorders, metabolic diseases and cancer by Vojtech Adam (236-236).
Metal ions play many key, crucial and even life-sustaining roles in organisms [1-6]. Despite the fact that experimental research is carried out in this area intensively for decades, it is clear that many biological properties of metal ions and compounds containing metal ions have not been fully clarified. Moreover, the interaction of ions of heavy metals with biologically active molecules can be used to monitor changes in organisms. One of the aims of this special issue is to give an overview of news from the field of metal ions and their functions and roles in cause, progression, treatment and diagnosis of some grave diseases and disorders. Moreover, the authors aim their attention to nanotechnologies and methods how to determine metal-based drugs in an organism. The special issue includes six papers from well known researchers in their fields. Hiroko Kodama and colleagues review inherited copper transport disorders . Disruptions to normal copper homeostasis are hallmarks of three genetic disorders: Menkes disease, occipital horn syndrome, and Wilson
Inherited Copper Transport Disorders: Biochemical Mechanisms, Diagnosis, and Treatment by Hiroko Kodama (237-250).
Copper is an essential trace element required by all living organisms. Excess amounts of copper, however, results in cellular damage. Disruptions to normal copper homeostasis are hallmarks of three genetic disorders: Menkes disease, occipital horn syndrome, and Wilson's disease. Menkes disease and occipital horn syndrome are characterized by copper deficiency. Typical features of Menkes disease result copper-dependent enzyme activity. Standard treatment involves parenteral administration of copper-histidine. If treatment is initiated before 2 months of age, neurodegeneration can be prevented, while delayed treatment is utterly ineffective. Thus, neonatal mass should be implemented. Meanwhile, connective tissue disorders cannot be improved by copper-histidine treatment. Combination with copper-histidine injections and oral administration of disulfiram is being investigated. Occipital horn syndrome characterized connective tissue abnormalities is the mildest form of Menkes disease. Treatment has not been conducted for this syndrome. Wilson's disease is characterized by copper toxicity that typically affects the hepatic and nervous systems severely. Various other symptoms are observed as well, yet its early diagnosis is sometimes difficult. Chelating agents and zinc are effective treatments, but are inefficient in most patients with fulminant hepatic failure. In addition, some patients with neurological Wilson's disease worsen or show poor response to chelating agents. Since early treatment is critical, a screening system for Wilson's disease should be implemented in infants. Patients with Wilson's disease may be at risk of developing hepatocellular carcinoma. Understanding the link between Wilson's disease and hepatocellular carcinoma will be beneficial for disease treatment and prevention.
Graphene, Carbon Nanotubes and Nanoparticles in Cell Metabolism by Martin Pumera (251-256).
Nanomaterials and nanotechnology is in forefront of materials research. Minimal attention is given to the potential participation of these materials in cell metabolism. Here we review recent efforts to understanding how carbon nanomaterials participate on cell metabolism. First, the introduction to the materials science of graphene, carbon nanotubes and metallic nanoparticles is give. Second, different mechanisms of participation of these materials on the cell metabolism are discussed and elucidated.
Long-term Exposure to Cadmium in Food and Cigarette Smoke, Liver Effects and Hepatocellular Carcinoma by Soisungwan Satarug (257-271).
Rising incidence of hepatocellular carcinoma (HCC) has been noted in recent years along with diabetes for which reasons and mechanisms are unclear. The rise in HCC is attributed to increasing rates of hepatitis C virus (HCV) infections while increases in diabetes are attributed to obesity. Increased HCC risk has also been noted in diabetes and obesity. Cadmium, a common food contaminant and a constituent of cigarette smoke, is one of ten chemicals considered by the World Health Organization to be of major public health concern. A correlation of cadmium intakes and increased HCC mortality risk has been noted in an ecological study while both hepatocellular carcinoma and hepatic adenoma occurred in cadmium-exposed mice. In the U.S. NHANES III, urinary cadmium levels, indicative of long-term exposure, have been associated with pre-diabetes and diabetes in a dose dependent manner. Intriguing possibility is that cadmium may increase HCC risk through increasing the frequency of hepatogenous diabetes. Overall aim of the present review is to explore if cadmium is a relevant risk factor in chronic liver disease and a rising HCC incidence. It will highlight cadmium levels detectable in various foods, livers, kidneys and urine samples of humans together with global health threat of ingested cadmium, pointing to measures for reducing exposure and a need for revision of guidelines for safe intake levels. Lastly, it will examine evidence for potential roles of cadmium in chronic liver diseases and HCC risk in a call for human case-control studies and animal experiments to elucidate underlying molecular mechanisms.
Analytical Approaches for Assaying Metallodrugs in Biological Samples: Recent Methodological Developments and Future Trends by Andrei Timerbaev (272-283).
Contemporary medicine increasingly relies on metal-based drugs and correspondingly growing in importance is the monitoring of the drugs and their metabolites in biological samples. Over the last decade, a range of analytical techniques have been developed in order to improve administration strategies for clinically approved compounds and understand pharmacokinetics, pharmacodynamics, and metabolism of new drugs so as ultimately to make their clinical development more effective. This paper gives an overview of various separation and detection methods, as well as common sample preparation strategies, currently in use to achieve the intended goals. The critical discussion of existing analytical technologies encompasses notably their detection capability, ability to handle biological matrices with minimum pretreatment, sample throughput, and cost efficiency. The main attention is devoted to those applications that are progressed to real-world biosamples and selected examples are given to illustrate the overall performance and applicability of advanced analytical systems. Also emphasized is the emerging role of inductively coupled plasma mass spectrometry (ICP-MS), both as a standalone instrument (for determination of metals originating from drug compounds) and as an element-specific detector in combinations with liquid chromatography or capillary electrophoresis (for drug metabolism studies). An increasing number of academic laboratories are using ICP-MS technology today, and this review will focus on the analytical possibilities of ICP-MS which would before long provide the method with the greatest impact on the clinical laboratory.
Molecular and Cellular Mechanisms of Hexavalent Chromium-Induced Lung Cancer: An Updated Perspective by A. M. Urbano (284-305).
For over a century, chromium (Cr) has found widespread industrial and commercial use, namely as a pigment, in the production of stainless steel and in chrome plating. The adverse health effects to the skin and respiratory tract of prolonged exposure to Cr have been known or suspected for a long time, but it was much more recently that the toxicity of this element was unequivocally attributed to its hexavalent state. Based on the combined results of extensive epidemiological studies, animal carcinogenicity studies and several types of other relevant data, authoritative regulatory agencies have found sufficient evidence to classify hexavalent chromium [Cr(VI)] compounds as encountered in the chromate production, chromate pigment production and chromium plating industries as carcinogenic to humans. Crucial for the development of novel strategies to prevent, detect and/or treat Cr(VI)-induced cancers is a detailed knowledge of the molecular and cellular mechanisms underlying these pathologies. Unfortunately, in spite of a considerable research effort, crucial facets of these mechanisms remain essentially unknown. This review is intended to provide a concise, integrated and critical perspective of the current state of knowledge concerning multiple aspects of Cr(VI) carcinogenesis. It will present recent theories of Cr(VI)-induced carcinogenesis and will include aspects not traditionally covered in other reviews, such as the possible involvement of the energy metabolism in this process. A brief discussion on the models that have been used in the studies of Cr(VI)-induced carcinogenicity will also be included, due to the impact of this parameter on the relevance of the results obtained.
From Amino Acids to Proteins as Targets for Metal-based Drugs by Ondrej Zitka (306-320).
Metallomics and metalloproteomics are emerging fields addressing the role, uptake, transport and storage of trace metals ions both toxic and essential for an organism. Research areas related to the understanding of the mechanisms of life processes associated to metals are covered. Similarly to the genome and proteome terms, metallome was introduced to refer to metalloproteins, metalloenzymes and other metal-containing biomolecules in a biological system. This review aims to give an overview of metal ions behaviour in organisms. The interactions of metals with biomolecules such as amino acids, peptides and protein are the main focus. Special attention is paid to the application of nanotechnology-based techniques using these interactions for medical purposes such as diagnostics, imaging and therapy.
Biological Implications of Oxidation and Unidirectional Chiral Inversion of D-amino Acids by Yong-Xiang Wang (321-331).
Recent progress in chiral separation of D- and L-amino acids by chromatography ascertained the presence of several free Damino acids in a variety of mammals including humans. Unidirectional chiral inversion of many D-amino acid analogs such as exogenous NG-nitro-D-arginine (D-NNA), endogenous D-leucine, D-phenylanine and D-methionine have been shown to take place with inversion rates of 4-90%, probably dependent on various species D-amino acid oxidase (DAAO) enzymatic activities. DAAO is known to catalyze the oxidative deamination of neutral and basic D-amino acids to their corresponding α-keto acids, hydrogen peroxide and ammonia, and is responsible for the chiral inversion. This review provides an overview of recent research in this area: 1) oxidation and chiral inversion of several D-amino acid analogs in the body; 2) the indispensable but insufficient role of DAAO particularly in the kidneys and brain for the oxidation and chiral inversion of D-amino acids analogs; and 3) unidentified transaminase(s) responsible for the second step of chiral inversion. The review also discusses the physiological significance of oxidation and chiral inversion of D-amino acids, which is still a subject of dispute.
Aspartate Aminotransferase - Bridging Carbohydrate and Energy Metabolism in Plasmodium Falciparum by Carsten Wrenger (332-336).
In this mini-review we briefly examine and summarize evidence on the role of the plasmodial aspartate aminotransferase (AspAT) of the malarial parasite. Recent data have provided information on the products of the purine salvage pathway as well as the glycolytic and oxidative phosphorylation pathways, suggesting that the reaction catalyzed by AspAT is an essential step in all these biochemical processes. While the biological role of the oxidative phosphorylation cycle still remains to be demonstrated, the presence of a single protein that is functional in multiple pathways (i.e. amino acid/purine/pyrimidine biosynthesis and carbohydrate metabolism) provides a high potential for the development of novel strategies to combat the spread of multi-drug resistant malaria.