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Archives of Toxicology (v.83, #7)

Predicting drug metabolism-dependent toxicity by Hermann M. Bolt; Jan G. Hengstler (pp. 635-638).

Low-dose extrapolation in toxicology: an old controversy revisited by Beate Pesch; Anne Spickenheuer; Dirk Taeger; Thomas Brüning (pp. 639-640).

Induced pluripotent stem cells: a new tool for toxicology screening? by Boon Chin Heng; Mark Richards; Yimin Shu; Philip Gribbon (pp. 641-644).

Comment on Slama R, Cyrys J, Herbarth O, Wichmann H-E, Heinrich J. saying: “The authors did not wish to reply, given Dr. Morfeld’s persistence in refusing to fill in the conflict of interest statement and in misleadingly quoting parts of the sentences of our publications” by Peter Morfeld (pp. 645-646).

Strain difference of cadmium-induced testicular toxicity in inbred Wistar–Imamichi and Fischer 344 rats by Hideaki Shimada; Rika Narumi; Masaaki Nagano; Akira Yasutake; Michael P. Waalkes; Yorishige Imamura (pp. 647-652).

Previously, we reported that Wistar–Imamichi (WI) rats are highly resistant to cadmium (Cd)-induced lethality and hepatotoxicity compared to Fischer 344 (F344) rats. Since the testes are one of the most sensitive organs to acute Cd toxicity, we examined possible strain-related differences in Cd-induced testicular toxicity between inbred WI and F344 rats. Rats were treated with a single dose of 0.5, 1.0 or 2.0 mg Cd/kg, as CdCl₂, sc and killed 24 h later. Cd at doses of 1.0 and 2.0 mg/kg induced severe testicular hemorrhage, as assessed by pathological and testis hemoglobin content, in F344 rats, but not WI rats. After Cd treatment (2.0 mg/kg), the testicular Cd content was significantly lower in WI rats than in the F344 rats, indicating a toxiokinetic mechanism for the observed strain difference. Thus, the remarkable resistance to Cd-induced testicular toxicity in WI rats is associated, at least in part, with lower testicular accumulation of Cd. When zinc (Zn; 10 mg/kg, sc) was administered in combination with Cd (2.0 mg/kg) to F344 rats, the Cd-induced increase in testicular hemoglobin content, indicative of hemorrhage, was significantly reduced. Similarly, the testicular Cd content was significantly decreased with Zn co-treatment compared to Cd treatment alone. Thus, it can be concluded that the testicular Cd accumulation partly competes with Zn transport systems and that these systems may play an important role in the strain-related differences in Cd-induced testicular toxicity between WI and F344 rats.

Keywords: Cd; Testicular toxicity; Strain difference; Rat; Zn

Low level and sub-chronic exposure to methylmercury induces hypertension in rats: nitric oxide depletion and oxidative damage as possible mechanisms by Denise Grotto; Michele M. de Castro; Gustavo R. M. Barcelos; Solange C. Garcia; Fernando Barbosa Jr. (pp. 653-662).

Increased risk of hypertension after methylmercury (MeHg) exposure has been suggested. However, the underlying mechanisms are not well explored. In this paper, we have analyzed whether sub-chronic exposure to MeHg increases systolic blood pressure even at very low levels. In addition, we analyzed if the methylmercury-induced hypertension is associated with a decreased plasmatic nitric oxide levels and with a dysregulation of the activities of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT), as well as the levels of MDA and glutathione. For this study, Wistar rats were treated with methylmercury chloride (100 μg/kg per day) or vehicle. Total treatment time was 100 days. Malondialdehyde (MDA) and circulating NOx levels and superoxide dismutase (SOD) and catalase (CAT) activities were determined in plasma, whereas glutathione levels were determined in erythrocytes. Our results show that long-term treatment at a low level of MeHg affected systolic blood pressure, increasing and reducing the levels of plasmatic MDA and NOx, respectively. However, the activity of SOD did not decrease in the MeHg exposed group when compared to the control. We found a negative correlation between plasmatic nitrite/nitrate (NOx) levels and systolic blood pressure (r = −0.67; P = 0.001), and a positive correlation between MDA and systolic blood pressure (r = 0.61; P = 0.03), thus suggesting increased inhibition of NO formation with the increase of hypertension. In conclusion, long-term exposure to a low dose of MeHg increases the systolic pressure and is associated, at least in part, with increased production of ROS as judged by increased production of malondialdehyde and depressed NO availability.

Keywords: Methylmercury; Oxidative stress; Nitric oxide; Cardiovascular disease

Association of hOGG1 genotype with life style and oxidative DNA damage among Chinese ethnic populations by Yuebin Ke; Zhunzhen Zhang; Youshen Jiang; Zhixiong Zhuang; Lu Li; Wenqing Lu; Tangchun Wu (pp. 663-668).

To assess the natural variation of hOGG1 gene and the gene–environmental interactions, the hOGG1 codon 326 polymorphism and urinary 8-OHdG levels were investigated in large samples (n = 953) of healthy individuals from five Chinese ethnic populations by using PCR-RFLP and HPLC-ECD. Life-style parameters under study were obtained through a questionnaire. The allelic frequencies of the hOGG1 gene in the Chinese populations were found to be 0.16 (Ser/Ser), 0.49 (Ser/Cys) and 0.35 (Cys/Cys), respectively. The frequencies of Ser326Cys polymorphism were significantly different among the five Chinese ethnic populations (P = 0.002). No association was found between the hOGG1 gene polymorphism and other life-style parameters except for the association between Ser326Cys and smoking (P = 0.027). A significant increase of urinary 8-OHdG level was observed in Cys326Cys allelic healthy subjects (P = 0.033). These results suggest that there are natural variations of hOGG1 gene among Chinese ethnic populations. Smoking relates to Cys/Cys polymorphism frequencies, and oxidative DNA damage is repaired less in individuals with the hOGG1 Cys326Cys genotype.

Keywords: DNA repair; hOGG1 ; Ser326Cys polymorphism; Life style; 8-OHdG; Ethnic populations

Discreplasminin, a plasmin inhibitor isolated from Tityus discrepans scorpion venom by Josmary Brazón; Gina D’Suze; Maria Lucia D’Errico; Carmen L. Arocha-Piñango; Belsy Guerrero (pp. 669-678).

Tityus discrepans venom (TdV) produces digestive hemorrhages, disseminated intravascular coagulation, alveoli fibrin deposition and/or prothrombin and partial thromboplastin time alterations in humans. T. discrepans venom presents an in vitro tissue plasminogen activator-like (tPA-like), fibrino(geno)lytic and plasmin inhibitory activities. The plasmin inhibitor, called discreplasminin, was isolated from TdV. Discreplasminin has a pI of 8.0 and a relative molecular weight of <6,000 Da. Discreplasminin and aprotinin strongly inhibited plasmin activity and moderately tPA activity, while epsilon amino caproic acid (EACA) moderately inhibited both enzymes. In presence and absence of fibrin, the plasmin generation by tPA was completely inhibited by aprotinin and discreplasminin. EACA in the absence of fibrin partially inhibited plasmin generation (37%); however, it produced a total inhibition of plasmin generation on a fibrin surface. The tPA-clot lysis assay showed that discreplasminin acts like aprotinin inducing a slight delay in lysis time and lysis rate; in contrast, EACA presented a total inhibitory effect on fibrin lysis. These results suggest that discreplasminin presents an anti-fibrinolytic mechanism similar to aprotinin. Discreplasminin probably interacts with the active sites of plasmin and tPA. The presence of discreplasminin and other similar components in scorpion venom could partially explain the generalized fibrin deposition which was found previously in rams.

Keywords: Scorpion; Fibrinolytic activity; Plasmin inhibitor; Tityus discrepans ; Animal venoms; Hemostasis

Immunotoxic changes associated with a 7-day oral exposure to perfluorooctanesulfonate (PFOS) in adult male C57BL/6 mice by Li Zheng; Guang-Hui Dong; Yi-He Jin; Qin-Cheng He (pp. 679-689).

Perfluorooctanesulfonate (PFOS) is a widespread contaminant in the environment, as well as in wildlife and in humans. Toxicity tests in rodents have raised concerns about potential developmental, reproductive, and systemic effects of PFOS. However, there is little information about the effect of PFOS on immune system. In this study, adult male C57BL/6 mice were given by gavage 0, 5, 20 or 40 mg PFOS/kg day⁻¹ for 7 days. The results showed that PFOS exposure decreased food intake and body weight and increased liver mass and serum corticosterone levels in a dose-dependent manner. Flow cytometry analysis showed that the number of lymphocytic subpopulation cells decreased significantly in 20 or 40 mg PFOS/kg day⁻¹ group in comparison with normal C57BL/6 mice. Treatment with PFOS also markedly depressed the natural killer (NK) cell activity, lymphocyte proliferation and the plaque-forming cell (PFC) response. These results indicate that PFOS exposure can affect the immunity function in mice.

Keywords: Perfluorooctanesulfonate; Lymphocyte proliferation; Immunity function

Investigation of the sensitising and cross-sensitising potential of textile dyes and β-lactam antibiotics using a biphasic mice local lymph node assay by Varun Ahuja; Clemens Schreiber; Thomas Platzek; Ralf Stahlmann (pp. 691-699).

We used a modified protocol of the murine local lymph node assay (LLNA) to study the cross-sensitising potential of (a) textile dye disperse yellow 3 and its metabolite 2-amino-p-cresol, (b) two antibiotics, penicillin G and cefotiam. The test substances were applied in a biphasic manner, i.e. first on the shaved skin of the back followed by application on the dorsal side of the ears after 2 weeks. The end-points analysed included thickness and weight of an ear-biopsy, weight and cell number of the draining lymph node, and lymphocyte cell surface markers analysed by flow-cytometry. Disperse yellow 3 and its metabolite significantly altered the various end-points at both the tested concentrations (0.5 and 1%), thus demonstrating the sensitising potential of the two substances. The cross-sensitisation study showed significant modulation in the tested variables in the treated group as compared to the control, signifying cross-sensitisation potential of the two substances. Penicillin G and cefotiam showed significant changes in various end-points, pointing towards their sensitising potential. However, even at 50% concentration of the β-lactams no significant change in any end-point indicating absence of cross-reactivity of the antibiotics was noticed. We conclude that a biphasic, modified protocol of the LLNA is a suitable approach to test for a cross-reactivity potential of two related compounds.

Keywords: 2-Amino-p-cresol; Cross-reactivity; Disperse yellow 3; LLNA; Textile dye; β-Lactam antibiotic

Metabolism-dependent hepatotoxicity of amodiaquine in glutathione-depleted mice by Shinji Shimizu; Ryo Atsumi; Kenichi Itokawa; Masaru Iwasaki; Takanori Aoki; Chiho Ono; Takashi Izumi; Kenichi Sudo; Osamu Okazaki (pp. 701-707).

We investigated the hepatotoxicity induced by AQ using a glutathione (GSH)-depleted mice model. Although sole administration of either AQ or l-buthionine-S,R-sulfoxinine (BSO), a well-known GSH synthesis inhibitor, produced no significant hepatotoxicity, combined administration of AQ with BSO induced hepatotoxicity characterized by centrilobular necrosis of the hepatocytes and an elevation of plasma alanine aminotransferase activity. Pretreatment of aminobenzotriazole, a nonspecific inhibitor for P450s, completely suppressed the above hepatotoxicity caused by AQ co-treatment with BSO. Administration of radiolabeled AQ in combination with BSO exhibited significantly higher covalent binding to mice liver proteins than that observed after sole dosing of radiolabeled AQ. The results obtained in this GSH-depleted animal model suggest that the reactive metabolite of AQ formed by hepatic P450 binds to liver proteins, and then finally leads to hepatotoxicity. These observations may help to understand the risk factors and the mechanism for idiosyncratic hepatotoxicity of AQ in humans.

Keywords: Amodiaquine; Glutathione; l-Buthionine-S,R-sulfoxinine; R-sulfoxinine; Covalent binding; Idiosyncratic; Hepatotoxicity

A rapid and easy to handle thermoluminescence based technique for evaluation of carbon tetrachloride-induced oxidative stress on rat hepatocytes by Anika Schumann; Alexander Bauer; Matthias Hermes; Matthias Gilbert; Jan G. Hengstler; Christian Wilhelm (pp. 709-720).

Oxidative stress has become one of the most intensively studied topics in biomedical research and is an often observed mechanism of non-genotoxic carcinogens like carbon tetrachloride. To monitor the oxidative stress status in in vitro hepatocytes, we compared thermoluminescence (TL) measurements with biochemical standard methods for oxidative stress markers. In contrast to biochemical analysis, TL measurements can be performed without any time-consuming extraction procedures by using directly collected cell material. After incubation with CCl₄ (24 h), thermo-induced light emission increased with rising concentration of CCl₄ up to eightfold at 10 mM CCl₄. Simultaneously, we determined the content of different secondary oxidative stress products, like thiobarbituric acid reactive substances and malondialdehyde. The rise of all biochemical markers complied with the increasing concentration of CCl₄. Finally, we could show that the CCl₄-induced increase of oxidative stress markers determined by time-consuming biochemical methods perfectly correlates with the increase of high temperature bands in rapid TL measurements.

Keywords: Thermoluminescence; Secondary lipid peroxidation products; Rat hepatocytes; Carbon tetrachloride

The benzene metabolite para-benzoquinone is genotoxic in human, phorbol-12-acetate-13-myristate induced, peripheral blood mononuclear cells at low concentrations by Götz Alexander Westphal; Jürgen Bünger; Nadine Lichey; Dirk Taeger; Angelika Mönnich; Ernst Hallier (pp. 721-729).

Benzene is one of the most prominent occupational and environmental pollutants. The substance is a proven human carcinogen that induces hematologic malignancies in humans, probably at even low doses. Yet knowledge of the mechanisms leading to benzene-induced carcinogenesis is still incomplete. Benzene itself is not genotoxic. The generation of carcinogenic metabolites involves the production of oxidized intermediates such as catechol, hydroquinone and para-benzoquinone (p-BQ) in the liver. Further activation to the ultimate carcinogenic intermediates is most probably catalyzed by myeloperoxidase (MPO). Yet the products of the MPO pathway have not been identified. If an oxidized benzene metabolite such as p-BQ was actually the precursor for the ultimate carcinogenic benzene metabolite and further activation proceeds via MPO mediated reactions, it should be possible to activate p-BQ to a genotoxic compound in vitro. We tested this hypothesis with phorbol-12-acetate-13-myristate (PMA) activated peripheral blood cells exposed to p-BQ, using the cytokinesis-block micronucleus test. Addition of 20–28 ng/ml PMA caused a significant increase of micronuclei at low and non-cytotoxic p-BQ concentrations between 0.04 and 0.2 μg/ml (0.37–1.85 μM). Thus with PMA or p-BQ alone no reproducible elevation of micronuclei was seen up to toxic concentrations. PMA and p-BQ induce micronuclei when administered jointly. Our results add further support to the hypothesis that MPO is a key enzyme in the activation of benzene.

Keywords: Benzene; para-Benzoquinone; Phorbol-12-acetate-13-myristate

N-Acetyl-S-(1-carbamoyl-2-hydroxy-ethyl)-l-cysteine (iso-GAMA) a further product of human metabolism of acrylamide: comparison with the simultaneously excreted other mercaptuic acids by Eva C. Hartmann; Melanie I. Boettcher; Hermann M. Bolt; Hans Drexler; Jürgen Angerer (pp. 731-734).

The N-acetyl-S-(1-carbamoyl-2-hydroxy-ethyl)-l-cysteine (iso-GAMA) could be identified as a further human metabolite of acrylamide. In this study, we report the excretion of d₃-iso-GAMA in human urine after single oral administration of deuterium labelled acrylamide (d₃-AA). One healthy male volunteer ingested a dose of about 1 mg d₃-AA which is equivalent to a dose of 13 μg/kg bodyweight. Over a period of 46 h the urine was collected and the d₃-iso-GAMA levels analysed by LC-ESI-MS/MS. The excretion of iso-GAMA begins five hours after application. It rises to a maximum concentration (c _max) of 43 μg/l which was quantified in the urine excreted after 22 h (t _max). The excretion pattern is parallel to that of the major oxidative metabolite N-acetyl-S-(2-carbamoyl-2-hydroxy-ethyl)-l-cysteine (GAMA). Total recovery of iso-GAMA was about 1% of the applied dose. Together with N-acetyl-S-(2-carbamoylethyl)-l-cysteine (AAMA) and GAMA, 57% of the applied dose is eliminated as mercapturic acids. The elimination kinetics of the three mercapturic acids of AA are compared. We show that dietary doses of acrylamide (AA) cause an overload of detoxification via AAMA and lead to the formation of carcinogenic glycidamide (GA) in the human body.

Keywords: Acrylamide; Glycidamide; Toxicokinetics; Metabolism

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Archives of Toxicology (v.83, #7)