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Archives of Toxicology (v.84, #8)

Severe arsenic poisoning: one of the largest man-made catastrophies by K. Golka; J. G. Hengstler; R. Marchan; H. M. Bolt (pp. 583-584).

Influence of arsenate and arsenite on signal transduction pathways: an update by Ingrid L. Druwe; Richard R. Vaillancourt (pp. 585-596).

Arsenic has been a recognized contaminant and toxicant, as well as a medicinal compound throughout human history. Populations throughout the world are exposed to arsenic and these exposures have been associated with a number of human cancers. Not much is known about the role of arsenic as a human carcinogen and more recently its role in non-cancerous diseases, such as cardiovascular disease, hypertension and diabetes mellitus have been uncovered. The health effects associated with arsenic are numerous and the association between arsenic exposure and human disease has intensified the search for molecular mechanisms that describe the biological activity of arsenic in humans and leads to the aforementioned disease states. Arsenic poses a human health risk due in part to the regulation of cellular signal transduction pathways and over the last few decades, some cellular mechanisms that account for arsenic toxicity, as well as, signal transduction pathways have been discovered. However, given the ubiquitous nature of arsenic in the environment, making sense of all the data remains a challenge. This review will focus on our knowledge of signal transduction pathways that are regulated by arsenic.

Keywords: Arsenic; Arsenite; Arsenate; Signal transduction

Combined ascorbate and glutathione deficiency leads to decreased cytochrome b ₅ expression and impaired reduction of sulfamethoxazole hydroxylamine by Sachin Bhusari; Mahmoud Abouraya; Marcia L. Padilla; Marie E. Pinkerton; Nicholas J. Drescher; James C. Sacco; Lauren A. Trepanier (pp. 597-607).

Sulfonamide antimicrobials such as sulfamethoxazole (SMX) have been associated with drug hypersensitivity reactions, particularly in patients with AIDS. A reactive oxidative metabolite, sulfamethoxazole-nitroso (SMX-NO), forms drug-tissue adducts that elicit a T-cell response. Antioxidants such as ascorbic acid (AA) and glutathione (GSH) reduce SMX-NO to the less reactive hydroxylamine metabolite (SMX-HA), which is further reduced to the non-immunogenic parent compound by cytochrome b ₅ (b5) and its reductase (b5R). We hypothesized that deficiencies in AA and GSH would enhance drug-tissue adduct formation and immunogenicity toward SMX-NO and that these antioxidant deficiencies might also impair the activity of the b5/b5R pathway. We tested these hypotheses in guinea pigs fed either a normal or AA-restricted diet, followed by buthionine sulfoximine treatment (250 mg/kg SC daily, or vehicle); and SMX-NO (1 mg/kg IP 4 days per week, or vehicle), for 2 weeks. Guinea pigs did not show any biochemical or histopathologic evidence of SMX-NO-related toxicity. Combined AA and GSH deficiency in this model did not significantly increase tissue-drug adduct formation, or splenocyte proliferation in response to SMX-NO. However, combined antioxidant deficiency was associated with decreased mRNA and protein expression of cytochrome b ₅, as well as significant decreases in SMX-HA reduction in SMX-NO-treated pigs. These results suggest that SMX-HA detoxification may be down-regulated in combined AA and GSH deficiency. This mechanism could contribute to the higher risk of SMX hypersensitivity in patients with AIDS with antioxidant depletion.

Keywords: Guinea pig; Antioxidants; Drug hypersensitivity; NADH hydroxylamine reductase

Simultaneous gene expression signature of heart and peripheral blood mononuclear cells in astemizole-treated rats by Eun-Hee Lee; Jung-Hwa Oh; Han-Jin Park; Do-Geun Kim; Jong-Hwa Lee; Choong-Yong Kim; Myung-Sang Kwon; Seokjoo Yoon (pp. 609-618).

We investigated the effects of astemizole, a second-generation antihistamine, on the heart and peripheral blood mononuclear cells (PBMCs) and identified the early markers of its cardiotoxicity using gene expression profiling. Astemizole causes torsades de pointes, which is a type of ventricular tachycardia. We administered astemizole (dosage: 20, 60 mg/kg) to male Sprague–Dawley rats, using an oral gavage. Cardiac tissue and PBMCs were collected from the rats 4 h after treatment. Gene expression profiles were obtained using an Affymetrix GeneChip. The most deregulated genes were associated with energy metabolism pathways and calcium ion homeostasis in the heart of astemizole-treated rats. The most altered genes in the PBMCs were those involved in developmental processes and cardiotoxicity. Genes related to the response to oxidative stress, reactive oxygen species, heat shock proteins, hypoxia, immunity, and inflammation were also deregulated in the heart and PBMCs. These data provide further insight into the genetic pathways affected by astemizole. In addition, the simultaneously deregulated genes identified herein may be further studied. It will be interesting to find out whether single genes or certain sets of these genes could finally serve as biomarkers for cardiotoxicity of astemizole or other similar antihistamine drugs.

Keywords: Astemizole; Ventricular tachycardia; Cardiotoxicity; Gene expression profiling

Regulation of dioxin receptor function by different beta-carboline alkaloids by Thomas Haarmann-Stemmann; Jandirk Sendker; Christine Götz; Nathalie Krug; Hanno Bothe; Ellen Fritsche; Peter Proksch; Josef Abel (pp. 619-629).

The dioxin receptor, also known as arylhydrocarbon receptor (AhR), is a ligand-activated transcription factor that mediates the toxicity of dioxins and related environmental contaminants. In addition, there is a growing list of natural compounds, mainly plant polyphenols that can modulate AhR function and downstream signaling with quite unknown consequences for cellular function. We investigate the potential of four different β-carboline alkaloids to stimulate AhR signaling in human hepatoma cells and keratinocytes. Three test substances, namely rutaecarpine, annomontine and xestomanzamine A, increase AhR-driven reporter gene activity as well as expression of two AhR target genes in a dose-dependent and time-dependent manner. Additionally, the three test alkaloids stimulate cytochrome P450 (CYP) 1 enzyme activity without showing any antagonistic effects regarding benzo(a)pyrene-stimulated CYP1 activation. The AhR-activating property of the β-carbolines is completely abrogated in AhR-deficient cells providing evidence that rutaecarpine, annomontine and xestomanzamine A are natural stimulators of the human AhR. The toxicological relevance of beta-carboline-mediated AhR activation is discussed.

Keywords: Arylhydrocarbon receptor; Benzo(a)pyrene; Beta-carboline alkaloids; Cytochrome P450

Pyrogallol-induced As4.1 juxtaglomerular cell death is attenuated by MAPK inhibitors via preventing GSH depletion by Yong Hwan Han; Woo Hyun Park (pp. 631-640).

Pyrogallol (PG) induces apoptosis in several types of cells mediated by superoxide anion (O ₂ ^•− ). Here, we investigated the effects of PG and/or MAPK (MEK, JNK, and p38) inhibitors on the changes in cell growth, cell death, reactive oxygen species (ROS), and GSH levels in As4.1 juxtaglomerular (JG) cells. PG inhibited the growth of As4.1 cells. It also induced apoptosis and the loss of mitochondrial membrane potential (MMP; ΔΨ_m) and increased the level of p53 protein. Intracellular O ₂ ^•− level was increased in PG-treated As4.1 cells. PG also increased the number of GSH deleted cells in As4.1 cells. All the MAPK inhibitors significantly attenuated the growth inhibition and death mediated by PG. They decreased the levels of p53 protein and MMP (ΔΨ_m) loss in PG-treated As4.1 cells. They also reduced O ₂ ^•− level and GSH-depleted cell number in these cells. In conclusion, MAPK inhibitors attenuated As4.1 cell growth inhibition and death mediated by PG treatment. The changes in O ₂ ^•− and GSH levels by PG and/or MAPK inhibitors appeared to affect the growth and death of As4.1 cells.

Keywords: Pyrogallol; Apoptosis; As4.1; MAPK; ROS; GSH

Beauvericin and ochratoxin A genotoxicity evaluated using the alkaline comet assay: single and combined genotoxic action by Maja Šegvić Klarić; Dina Daraboš; Ružica Rozgaj; Vilena Kašuba; Stjepan Pepeljnjak (pp. 641-650).

This study was aimed at investigating the genotoxic potential of single beauvericin (BEA) and ochratoxin A (OTA) as well as their interaction in porcine kidney epithelial PK15 cells and human leukocytes using the alkaline comet assay. IC₅₀ of BEA (5.0 ± 0.6) and OTA (15.8 ± 1.5) estimated by MTT reduction assay shows that BEA is three times more toxic than OTA. BEA (0.1 and 0.5 μM) and OTA (1 and 5 μM) were applied alone or in combination of these concentrations for 1 and 24 h in PK15 cells and human leukocytes. Genotoxicity of these toxins to PK15 cells was time- and concentration dependent. After 1 h, significant increase in tail length, tail intensity, tail moment, and abnormal sized tails (AST) was noted upon exposure to 1 μM of OTA alone and BEA + OTA combinations. Single BEA (0.5 μM) and OTA (1 and 5 μM) and their combinations evoked significant DNA damage in PK15 cells, considering all comet tail parameters measured after 24 h of treatment. Human leukocytes were slightly concentration but not time dependent. After 1 h of exposure, there were no significant changes in the tail length. Tail intensity, tail moment, and/or incidence of AST were significantly higher in cells treated with single OTA or BEA and their combinations than in control cells. DNA damage in leukocytes was significantly higher after 24 h of exposure to single toxins and their combinations, considering all comet tail parameters, but these changes were less pronounced than in PK15 cells. Combined toxins showed additive and synergistic effects in PK15 cells, while only additive effects were observed in human leukocytes. Combined prolonged exposure to BEA and OTA in subcytotoxic concentrations through food consumption could induce DNA damage contributing to the carcinogenicity in animals and humans.

Keywords: Genotoxicity; Comet assay; Mycotoxin synergism; Carcinogenicity

Potential roles of fibroblast growth factor-9 in the benzo(a)pyrene-induced invasion in vitro and the metastasis of human lung adenocarcinoma by Tzuu-Huei Ueng; Yih-Leong Chang; Yi-Ya Tsai; Jen-Liang Su; Ping-Kun Chan; Jin-Yuan Shih; Yung-Chie Lee; Yee-Chung Ma; Min-Liang Kuo (pp. 651-660).

Fibroblast growth factor (FGF)-9 belongs to the FGF family which modulate cell proliferation, differentiation, and motility. Benzo(a)pyrene is a polycyclic aromatic hydrocarbon (PAH) and ubiquitous environmental carcinogen present in automobile exhaust, cigarette smoke, and foods. The major purposes of this study were to explore the roles of FGF-9 in the benzo(a)pyrene-induced lung cancer invasion in vitro and the metastatic development of lung adenocarcinoma in human. The data of RT-PCR analysis indicated that treatments of human lung adenocarcinoma CL5 cells with benzo(a)pyrene and a PAH mixture motorcycle exhaust particulate (MEP) extracts increased FGF-9 mRNA expression. The increased expression was blocked by cotreatments with a p38 mitogen-activated protein kinase inhibitor SB202190 and an extracellular signal-regulated kinase inhibitor PD98059. The results of immunoblot analysis and Matrigel assay showed that benzo(a)pyrene and MEP extracts produced a concomitant induction of FGF-9 protein and invasive ability of CL5 cells. The benzo(a)pyrene- and MEP-induced invasion was suppressed by FGF-9 neutralizing antibodies. The results of immunohistochemistry analysis of human lung adenocarcinoma specimens showed that FGF-9 protein was detected in the adenocarcinoma cells but not in normal epithelium. FGF-9 staining intensity was positively correlated with status of disease and degree of lymph node metastasis in these lung adenocarcinomas. These present findings suggest that FGF-9 has potential roles in benzo(a)pyrene-induced CL5 cell invasion and human lung adenocarcinoma metastasis.

Keywords: FGF-9; Benzo(a)pyrene; Lung adenocarcinoma; Invasion; Metastasis

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Archives of Toxicology (v.84, #8)