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Archives of Toxicology (v.85, #3)
Contrast agent-induced nephrotoxicity: role of oxidative stress and apoptosis through the mitochondrial pathway
by J. D. Stewart; J. G. Hengstler; H. M. Bolt (pp. 163-164).
Nephrotoxicity of contrast media and protective effects of acetylcysteine by Carlo Briguori; Cristina Quintavalle; Francesca De Micco; Gerolama Condorelli (pp. 165-173).
Contrast-induced acute kidney injury (CI-AKI) accounts for approximately 10% of all causes of hospital-acquired renal failure, causes a prolonged in-hospital stay, and represents a powerful predictor of poor early and late outcome. N-acetylcysteine (NAC) is a thiol compound classically known as a mucolytic agent, which is a potent antioxidant that scavenges a wide variety of oxygen-derived-free-radicals and may be capable of preventing acute kidney injury. In the present study, we will review (1) the pathophysiology of the CI-AKI and (2) the experimental and clinical data on the effects of NAC in preventing CI-AKI.
Keywords: Kidney; Contrast media; NAC; Apoptosis; Acetylcysteine
Erratum to: Nephrotoxicity of contrast media and protective effects of acetylcysteine
by Carlo Briguori; Cristina Quintavalle; Francesca De Micco; Gerolama Condorelli (pp. 175-175).
Effects of exogenous glutathione on arsenic burden and NO metabolism in brain of mice exposed to arsenite through drinking water by Yan Wang; Fenghong Zhao; Yaping Jin; Yuan Zhong; Xiaoyun Yu; Gexin Li; Xiuqiang Lv; Guifan Sun (pp. 177-184).
Chronic exposure to inorganic arsenic (iAs) is associated with neurotoxicity. Studies to date have disclosed that methylation of ingested iAs is the main metabolic pathway, and it is a process relying on reduced glutathione (GSH). The aim of this study was to explore the effects of exogenous GSH on arsenic burden and metabolism of nitric oxide (NO) in the brain of mice exposed to arsenite via drinking water. Mice were exposed to sodium arsenite through drinking water contaminated with 50 mg/L arsenic for 4 weeks and treated intraperitoneally with saline solution, 200 mg/kg body weight (b.w), 400 mg/kg b.w, or 800 mg/kg b.w GSH, respectively, at the 4th week. Levels of iAs, monomethylarsenic acid, and dimethylarsenic acid (DMAs) in the liver, blood, and brain were determined by method of hydride generation coupled with atomic absorption spectrophotometry. Activities of nitric oxide synthase (NOS) and contents of NO in the brain were determined by colorimetric method. Compared with mice exposed to arsenite alone, administration of GSH increased dose-dependently the primary and secondary methylation ratio in the liver, which caused the decrease in percent iAs and increase in percent DMAs in the liver, as a consequence, resulted in significant decrease in iAs levels in the blood and total arsenic levels in both blood and brain. NOS activities and NO levels in the brain of mice in iAs group were significantly lower than those in control; however, administration of GSH could increase significantly activities of NOS and contents of NO. Findings from this study suggested that exogenous GSH could promote both primary and secondary arsenic methylation capacity in the liver, which might facilitate excretion of arsenicals, and consequently reduce arsenic burden in both blood and brain and furthermore ameliorate the effects of arsenicals on NO metabolism in the brain.
Keywords: Arsenite; Glutathione; Arsenic methylation; Nitric oxide synthase; Nitric oxide
Performance of biomarkers SMRP, CA125, and CYFRA 21-1 as potential tumor markers for malignant mesothelioma and lung cancer in a cohort of workers formerly exposed to asbestos by M. Gube; D. Taeger; D. G. Weber; B. Pesch; P. Brand; G. Johnen; A. Müller-Lux; I. M. Gross; T. Wiethege; A. Weber; H. J. Raithel; T. Kraus; T. Brüning (pp. 185-192).
The aim of the study is to examine the cancer-predictive values of SMRP (soluble mesothelin-related peptides), CA125, and CYFRA21-1 as potential tumor markers for lung cancer and malignant mesothelioma in a cohort of workers formerly exposed to asbestos. A voluntary surveillance program has been established for German workers with former asbestos exposure. A subgroup of 626 subjects with a mean age of 63 years (range 53–70 years) at baseline was enrolled in an extended health examination program with high-resolution computer tomography (HRCT) of the chest and blood drawing between 1993 and 1997. Serum concentrations of SMRP, CA125, and CYFRA21-1 were measured in archived serum samples in 2005 and 2006. A mortality follow-up was conducted through 2007. So far, 12 cases with lung cancer and 20 cases with malignant mesothelioma have been observed in this cohort. The average time between sample collection and diagnosis was 4.7 years. Analyzed biomarkers showed low sensitivities (5–25%) and positive predictive values (4–30%) for both cancer sites. Marker combinations resulted in sensitivities between 5 and 50% and positive predictive values ranging from 3 to 14%. Even in those cases, where biomarker concentrations were available within 36 months before diagnosis, no trend for increasing biomarker levels was observed. The analyzed tumor markers were characterized by high specificities, but low sensitivities. SMRP, CA125, and CYFRA21-1 alone or in combination were less suitable to serve as predictors for the diagnosis of lung cancer or malignant mesothelioma. However, a prospective study with annual sampling might reveal a better predictive value of these markers.
Keywords: Tumor marker; SMRP; Mesothelioma; Lung cancer; Asbestos exposure
Effect of different buffers on kinetic properties of human acetylcholinesterase and the interaction with organophosphates and oximes by T. Wille; H. Thiermann; F. Worek (pp. 193-198).
Acetylcholinesterase (AChE) is the primary target of organophosphorus compounds (OP). The investigation into interactions between AChE, OP and oximes in vitro may be affected by the experimental conditions, e.g. by the buffer system. Hence, it was tempting to investigate the Michaelis–Menten kinetics and the inhibition and reactivation kinetics of paraoxon-ethyl, sarin, soman and VX in the presence of phosphate, MOPS, Tyrode and TRIS buffer with human AChE. Compared to phosphate buffer, the inhibition and reactivation kinetics of human erythrocyte AChE were markedly changed by TRIS and in part by MOPS, whereas Tyrode showed similar results to phosphate buffer. These results indicate an effect of the tested buffers on the properties of AChE, and an interaction between OP and oximes has to be considered for the design of in vitro studies and may impair the comparison of data from different laboratories. In view of the comparability of human in vitro kinetic data determined with phosphate buffer with data from human OP poisoning, it seems to be a suitable buffer for the investigation into interactions between AChE, OP and oximes.
Keywords: Acetylcholinesterase; Buffer; Kinetics; Organophosphorus compound; Inhibition; Reactivation
Stimulation of pro-inflammatory responses by mebendazole in human monocytic THP-1 cells through an ERK signaling pathway by Katsuhiko Mizuno; Yasuyuki Toyoda; Tatsuki Fukami; Miki Nakajima; Tsuyoshi Yokoi (pp. 199-207).
Oral helminthic mebendazole (MBZ) has been reported to cause liver injury with inflammatory responses. However, the underlying mechanism remains unknown. To examine the inflammatory reactions, we investigated whether MBZ and other helminthic drugs increase the release of pro-inflammatory cytokines and chemokines using human monocytic cells. The release of interleukin (IL)-8 and tumor necrosis factor (TNF) α from human monocytic THP-1 cells was significantly increased by treatment with MBZ, albendazole (ABZ), fenbendazole (FBZ), or oxibendazole (OBZ), but not by albendazole sulfoxide or praziquantel, suggesting that MBZ and structurally similar drugs can stimulate monocytes and increase the release of pro-inflammatory cytokines. MBZ also significantly increased the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and c-Jun N-terminal kinase (JNK) 1/2 in THP-1 cells. Pretreatment with the MAP kinase/ERK kinase 1/2 inhibitor U0126 significantly suppressed the increase of IL-8 and TNFα levels by MBZ, ABZ, FBZ, or OBZ treatment in THP-1 cells, but the p38 mitogen-activated protein kinase inhibitor SB203580 or JNK1/2 inhibitor SP600125 did not. These results suggested that an ERK1/2 pathway plays an important role in the release of IL-8 and TNFα in THP-1 cells treated with MBZ and structurally similar drugs. In conclusion, the release of inflammatory mediators by MBZ might be one of the mechanisms underlying immune-mediated liver injury. This in vitro method may be useful to predict adverse inflammatory reactions that lead to hepatotoxicity.
Keywords: Mebendazole; THP-1 cell; Hepatotoxicity; IL-8; TNFα
Lipopolysaccharide induces apoptotic insults to human alveolar epithelial A549 cells through reactive oxygen species-mediated activation of an intrinsic mitochondrion-dependent pathway by Chi-Yuan Chuang; Ta-Liang Chen; Yih-Giun Cherng; Yu-Tyng Tai; Tyng-Guey Chen; Ruei-Ming Chen (pp. 209-218).
Alveolar type II epithelial cells can regulate immune responses to sepsis-induced acute lung injury. Lipopolysaccharide (LPS), an outer membrane component of Gram-negative bacteria, can cause septic shock. This study was designed to evaluate the cytotoxic effects of LPS on human alveolar epithelial A549 cells and its possible molecular mechanisms. Exposure of A549 cells to LPS decreased cell viability in concentration- and time-dependent manners. In parallel, LPS concentration- and time-dependently induced apoptosis of A549 cells. Meanwhile, LPS only at a high concentration of 10 μg/ml caused mildly necrotic insults to A549 cells. In terms of the mechanism, exposure of A549 cells to LPS increased the levels of cellular nitric oxide and reactive oxygen species (ROS). Pretreatment with N-acetylcysteine (NAC), an antioxidant, significantly lowered LPS-caused enhancement of intracellular ROS in A549 cells and simultaneously attenuated the apoptotic insults. Sequentially, treatment of A549 cells with LPS caused significant decreases in the mitochondrial membrane potential and biosynthesis of adenosine triphosphate. In succession, LPS triggered the release of cytochrome c from the mitochondria to the cytoplasm. Activities of caspase-9 and caspase-6 were subsequently augmented following LPS administration. Consequently, exposure of A549 cells induced DNA fragmentation in a time-dependent manner. Pretreatment of A549 cells with NAC significantly ameliorated LPS-caused alterations in caspase-9 activation and DNA damage. Therefore, this study shows that LPS specifically induces apoptotic insults to human alveolar epithelial cells through ROS-mediated activation of the intrinsic mitochondrion–cytochrome c-caspase protease mechanism.
Keywords: Alveolar epithelial cells; Lipopolysaccharide; Reactive oxygen species; Apoptosis; Intrinsic mechanism
Titanium dioxide inclusion in backing reduce the photoallergenicity of ketoprofen transdermal patch by Yang-Gyu Choi; Ji Hae Lee; Il-Hong Bae; Young-Chang Ah; Han-Moe Ki; Jun-Ho Bae; Young-Ho Park; Kang Choon Lee; Kyung-Min Lim (pp. 219-226).
Ketoprofen (KP) is a widely used transdermal non-steroidal anti-inflammatory drug. However, increasing number of adverse effect case reports suggests that KP transdermal formulation can cause photoallergic reaction. The photoallergic potential of KP is attributable to the instability of KP under UV/visible light and subsequent formation of reactive degradation products. In this study, we investigated whether the inclusion of titanium dioxide (TiO2), a well-known mineral sunscreen agent, in the KP transdermal patch can prevent the photodegradation of KP and ultimately, can reduce photoallergic reaction. TiO2 inclusion in fabric backing effectively decreased the UV transmission through fabric patch throughout all UVA region from 320 to 380 nm and consistently, KP patch with TiO2 exhibited significantly increased photostability of KP. This enhanced photostability of KP resulted in reduced generation of photodegradation product as determined by HPLC–UV analysis. In a good accordance with these in vitro results, photosensitization test in guinea pig in vivo demonstrated low photoallergic reactions of KP patch with TiO2 compared to KP patch without TiO2, indeed. This study demonstrated that KP transdermal patch with TiO2-included backing can provide with improved photostability and photosafety over conventional fabric KP patch.
Keywords: Ketoprofen; Transdermal; Photoallergy; Phototoxicity; Photodegradation; Titanium dioxide
Treatment efficacy in a soman-poisoned guinea pig model: added value of physostigmine? by Marloes J. A. Joosen; August B. Smit; Herman P. M. van Helden (pp. 227-237).
Current treatment of organophosphate poisoning is insufficient, and survivors may suffer from long-lasting adverse effects, such as cognitive deficits and sleep-wake disturbances. In the present study, we aimed at developing a guinea pig model to investigate the benefits of immediate and delayed stand-alone therapy on the development of clinical signs, EEG, heart rate, respiration and AChE activity in blood and brain after soman poisoning. The model allowed the determination of the therapeutic effects at the short-term of obidoxime, atropine and physostigmine. Obidoxime exerted the highest therapeutic efficacy at administration of the lowest dose (3.1 mg/kg i.m.), whereas two higher doses (9 and 18 mg/kg) were less effective on most parameters. Addition of atropine at 0.03 and 3 mg/kg (i.m.) to the treatment did not improve the therapeutic effects of obidoxime alone. Physostigmine (0.8 mg/kg im) at 1 min after poisoning increased mortality. Two lower doses (0.1 and 0.3 mg/kg i.m.) showed improvements on all parameters but respiration. The middle dose was most effective in preventing seizure development and therefore assessed as the most efficacious dose. Combined treatment of obidoxime and physostigmine shortened the duration of seizures, if present, from up to 80 min to ~10–15 min. In practice, treatment will be employed when toxic signs appear, with the presence of high levels of AChE inhibition in both blood and brain. Administration of physostigmine at that moment showed to be redundant or even harmful. Therefore, treatment of OP poisoning with a carbamate, such as physostigmine, should be carefully re-evaluated.
Keywords: Soman; Physostigmine; Organophosphate; Seizures; Obidoxime