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Archives of Toxicology (v.86, #8)
Waterpipe smoking: a new tobacco pandemic entailing severe health risks?
by Andreas Luch (pp. 1161-1162).
Toxicogenomic-based approaches predicting liver toxicity in vitro
by P. Godoy; H. M. Bolt (pp. 1163-1164).
Progress in gene expression profiling by the introduction of metagenes
by R. Marchan; H. M. Bolt (pp. 1165-1166).
Toxicity of amphetamines: an update by Márcia Carvalho; Helena Carmo; Vera Marisa Costa; João Paulo Capela; Helena Pontes; Fernando Remião; Félix Carvalho; Maria de Lourdes Bastos (pp. 1167-1231).
Amphetamines represent a class of psychotropic compounds, widely abused for their stimulant, euphoric, anorectic, and, in some cases, emphathogenic, entactogenic, and hallucinogenic properties. These compounds derive from the β-phenylethylamine core structure and are kinetically and dynamically characterized by easily crossing the blood–brain barrier, to resist brain biotransformation and to release monoamine neurotransmitters from nerve endings. Although amphetamines are widely acknowledged as synthetic drugs, of which amphetamine, methamphetamine, and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) are well-known examples, humans have used natural amphetamines for several millenniums, through the consumption of amphetamines produced in plants, namely cathinone (khat), obtained from the plant Catha edulis and ephedrine, obtained from various plants in the genus Ephedra. More recently, a wave of new amphetamines has emerged in the market, mainly constituted of cathinone derivatives, including mephedrone, methylone, methedrone, and buthylone, among others. Although intoxications by amphetamines continue to be common causes of emergency department and hospital admissions, it is frequent to find the sophism that amphetamine derivatives, namely those appearing more recently, are relatively safe. However, human intoxications by these drugs are increasingly being reported, with similar patterns compared to those previously seen with classical amphetamines. That is not surprising, considering the similar structures and mechanisms of action among the different amphetamines, conferring similar toxicokinetic and toxicological profiles to these compounds. The aim of the present review is to give an insight into the pharmacokinetics, general mechanisms of biological and toxicological actions, and the main target organs for the toxicity of amphetamines. Although there is still scarce knowledge from novel amphetamines to draw mechanistic insights, the long-studied classical amphetamines—amphetamine itself, as well as methamphetamine and MDMA, provide plenty of data that may be useful to predict toxicological outcome to improvident abusers and are for that reason the main focus of this review.
Keywords: Amphetamines; Amphetamine; Methamphetamine; 3,4-Methylenedioxymethamphetamine; Pharmacokinetics; Hyperthermia; Oxidative stress; Neurotoxicity; Cardiovascular toxicity; Hepatotoxicity; Rhabdomyolysis; Nephrotoxicity
Cisplatin-induced nephrotoxicity and targets of nephroprotection: an update by Neife Aparecida Guinaim dos Santos; Maria Augusta Carvalho Rodrigues; Nadia Maria Martins; Antonio Cardozo dos Santos (pp. 1233-1250).
Cisplatin is a highly effective antitumor agent whose clinical application is limited by the inherent nephrotoxicity. The current measures of nephroprotection used in patients receiving cisplatin are not satisfactory, and studies have focused on the investigation of new possible protective strategies. Many pathways involved in cisplatin nephrotoxicity have been delineated and proposed as targets for nephroprotection, and many new potentially protective agents have been reported. The multiple pathways which lead to renal damage and renal cell death have points of convergence and share some common modulators. The most frequent event among all the described pathways is the oxidative stress that acts as both a trigger and a result. The most exploited pathways, the proposed protective strategies, the achievements obtained so far as well as conflicting data are summarized and discussed in this review, providing a general view of the knowledge accumulated with past and recent research on this subject.
Keywords: Cisplatin; Nephrotoxicity; Nephroprotection; Oxidative stress; Apoptosis; Molecular mechanisms; Mitochondria
Systems biology tools for toxicology by Suzanne Geenen; Peter Neal Taylor; Jacky L. Snoep; Ian D. Wilson; J. Gerry Kenna; Hans V. Westerhoff (pp. 1251-1271).
An important goal of toxicology is to understand and predict the adverse effects of drugs and other xenobiotics. For pharmaceuticals, such effects often emerge unexpectedly in man even when absent from trials in vitro and in animals. Although drugs and xenobiotics act on molecules, it is their perturbation of intracellular networks that matters. The tremendous complexity of these networks makes it difficult to understand the effects of xenobiotics on their ability to function. Because systems biology integrates data concerning molecules and their interactions into an understanding of network behaviour, it should be able to assist toxicology in this respect. This review identifies how in silico systems biology tools, such as kinetic modelling, and metabolic control, robustness and flux analyse, may indeed help understanding network-mediated toxicity. It also shows how these approaches function by implementing them vis-à-vis the glutathione network, which is important for the detoxification of reactive drug metabolites. The tools enable the appreciation of the steady state concept for the detoxification network and make it possible to simulate and then understand effects of perturbations of the macromolecules in the pathway that are counterintuitive. We review how a glutathione model has been used to explain the impact of perturbation of the pathway at various molecular sites, as would be the effect of single-nucleotide polymorphisms. We focus on how the mutations impact the levels of glutathione and of two candidate biomarkers of hepatic glutathione status. We conclude this review by sketching how the various systems biology tools may help in the various phases of drug development in the pharmaceutical industry.
Keywords: Systems biology; Toxicology; Computational tools; Glutathione; Paracetamol toxicity; Biomarkers
Non-animal test methods for predicting skin sensitization potentials by Annette Mehling; Tove Eriksson; Tobias Eltze; Susanne Kolle; Tzutzuy Ramirez; Wera Teubner; Bennard van Ravenzwaay; Robert Landsiedel (pp. 1273-1295).
Contact allergies are complex diseases, and it is estimated that 15–20 % of the general population suffers from contact allergy, with increasing prevalence. Evaluation of the sensitization potential of a substance is usually carried out in animal models. Nowadays, there is much interest in reducing and ultimately replacing current animal tests. Furthermore, as of 2013, the EU has posed a ban on animal testing of cosmetic ingredients that includes skin sensitization. Therefore, predictive and robust in vitro tests are urgently needed. In order to establish alternatives to animal testing, the in vitro tests must mimic the very complex interactions between the sensitizing chemical and the different parts of the immune system. This review article summarizes recent efforts to develop in vitro tests for predicting skin sensitizers. Cell-based assays, in chemico methods and, to a lesser extent, in silico methods are presented together with a discussion of their current status. With considerable progress having been achieved during the last years, the rationale today is that data from different non-animal test methods will have to be combined in order to obtain reliable hazard and potency information on potential skin sensitizers.
Keywords: Skin sensitization; Contact allergy; Alternative methods; In vitro testing; 3Rs principle
Suppression of nanosilica particle-induced inflammation by surface modification of the particles by Tomohiro Morishige; Yasuo Yoshioka; Hiroshi Inakura; Aya Tanabe; Shogo Narimatsu; Xinglei Yao; Youko Monobe; Takayoshi Imazawa; Shin-ichi Tsunoda; Yasuo Tsutsumi; Yohei Mukai; Naoki Okada; Shinsaku Nakagawa (pp. 1297-1307).
It has gradually become evident that nanomaterials, which are widely used in cosmetics, foods, and medicinal products, could induce substantial inflammation. However, the roles played by the physical characteristics of nanomaterials in inflammatory responses have not been elucidated. Here, we examined how particle size and surface modification influenced the inflammatory effects of nanosilica particles, and we investigated the mechanisms by which the particles induced inflammation. We compared the inflammatory effects of silica particles with diameters of 30–1,000 nm in vitro and in vivo. In macrophages in vitro, 30- and 70-nm nanosilica particles (nSP30 and nSP70) induced higher production of tumor necrosis factor-α (TNFα) than did larger particles. In addition, intraperitoneal injection of nSP30 and nSP70 induced stronger inflammatory responses involving cytokine production than did larger particles in mice. nSP70-induced TNFα production in macrophage depended on the production of reactive oxygen species and the activation of mitogen-activated protein kinases (MAPKs). Furthermore, nSP70-induced inflammatory responses were dramatically suppressed by surface modification of the particles with carboxyl groups in vitro and in vivo; the mechanism of the suppression involved reduction in MAPK activation. These results provide basic information that will be useful for the development of safe nanomaterials.
Keywords: Inflammation; Macrophage; Nanoparticle; Silica; Surface modification
Waterpipe smoking: the role of humectants in the release of toxic carbonyls by Jens Schubert; Volkmar Heinke; Jana Bewersdorff; Andreas Luch; Thomas G. Schulz (pp. 1309-1316).
In recent years, the number of waterpipe smokers has increased substantially worldwide. Here, we present a study on the identification and quantification of seven carbonylic compounds including formaldehyde, acetaldehyde and acrolein in the mainstream smoke of the waterpipe. Smoking was conducted with a smoking machine, and carbonyls were scavenged from the smoke with two impingers containing an acidic solution of 2,4-dinitrophenylhydrazine. The derivatives were then analyzed by high-performance liquid chromatography–tandem mass spectrometry (LC–MS/MS). For instance, during one waterpipe smoking session, up to 111 ± 12 μg formaldehyde could be detected. This value is about 5 times higher when compared to one 2R4F reference cigarette. We also found a distinct filter effect of the bowl water for all carbonyls investigated. Our data further demonstrate that increasing amounts of humectants in the unburned tobacco lowers the temperature in the waterpipe head during smoking, thereby resulting in decreasing levels of carbonyls in the smoke produced. Altogether, considerable amounts of toxic carbonyls are present in the waterpipe smoke, thus conferring a health risk to waterpipe smokers.
Keywords: Waterpipe; Carbonyls; Formaldehyde; Humectants; LC–MS/MS
Internal exposure to carcinogenic polycyclic aromatic hydrocarbons and DNA damage: a null result in brief
by Heiko U. Käfferlein; Boleslaw Marczynski; Patrice Simon; Jürgen Angerer; Hans-Peter Rihs; Michael Wilhelm; Kurt Straif; Beate Pesch; Thomas Brüning (pp. 1317-1321).
Biology and function of the aryl hydrocarbon receptor: report of an international and interdisciplinary conference by Charlotte Esser (pp. 1323-1329).
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor present in many cells. The AhR links environmental chemical stimuli with adaptive responses, such as detoxification, cellular homoeostasis or immune responses. Furthermore, novel roles of AhR in physiological and genetic functions are being discovered. This is a report of a recent meeting in Düsseldorf. The meeting highlighted that AhR research has moved from its focus on toxic effects of dioxins and other environmental pollutants to its biological roles. For instance, it was recently discovered that AhR-responsive elements in retrotransposons contribute to the functional structure of the genome. Other exciting new reports concerned the way plant-derived compounds in our diet are necessary for a fully functioning immune system of the gut. Also, human brain tumours use the AhR system to gain growth advantages. Other aspects covered were neurotoxicology, the circadian rhythm, or the breadth of the adaptive and innate immune system (hematopoietic stem cells, dendritic cells, T cells, mast cells). Finally, the meeting dealt with the discovery of new xenobiotic and natural ligands and their use in translational medicine, or cancer biology and AhR.
Keywords: Dioxin; Retrotransposons; Diet; Signalling crosstalk; Immune system; FICZ; Mast cells; Neurotoxicology; TDO