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Archives of Toxicology (v.83, #6)

Alcohol-induced liver injury: how a small molecule overwhelms one of the cell types with the best regeneration capacity of the human body by Jan G. Hengstler; Patricio Godoy; Joanna D. Stewart; Hermann M. Bolt (pp. 513-514).

Letter to the Editor by Rémy Slama (pp. 515-515).

Comment on Slama R, Cyrys J, Herbarth O, Wichmann H-E, Heinrich J. (2009) A further plea for rigorous science and explicit disclosure of potential conflicts of interest. Morfeld P. (2009) A plea for rigorous and honest science—false positive findings and biased presentations in epidemiological studies. Archives of Toxicology 83:105–106 by Peter Morfeld (pp. 517-518).

Role of oxidative stress in alcohol-induced liver injury by Arthur I. Cederbaum; Yongke Lu; Defeng Wu (pp. 519-548).

Reactive oxygen species (ROS) are highly reactive molecules that are naturally generated in small amounts during the body’s metabolic reactions and can react with and damage complex cellular molecules such as lipids, proteins, or DNA. Acute and chronic ethanol treatments increase the production of ROS, lower cellular antioxidant levels, and enhance oxidative stress in many tissues, especially the liver. Ethanol-induced oxidative stress plays a major role in the mechanisms by which ethanol produces liver injury. Many pathways play a key role in how ethanol induces oxidative stress. This review summarizes some of the leading pathways and discusses the evidence for their contribution to alcohol-induced liver injury. Special emphasis is placed on CYP2E1, which is induced by alcohol and is reactive in metabolizing and activating many hepatotoxins, including ethanol, to reactive products, and in generating ROS.

Keywords: Oxidative stress; Alcoholic liver injury; Reactive oxygen species; Antioxidants; CYP2E1; TNFα

Transplacental and early life exposure to inorganic arsenic affected development and behavior in offspring rats by Shuhua Xi; Wenjuan Sun; Fengzhi Wang; Yaping Jin; Guifan Sun (pp. 549-556).

To evaluate the developmental neurotoxicity of arsenic in offspring rats by transplacental and early life exposure to sodium arsenite in drinking water, the pregnant rats or lactating dams, and weaned pups were given free access to drinking water, which contained arsenic at concentrations of 0, 10, 50, 100 mg/L from GD 6 until PND 42. A battery of physical and behavioral tests was applied to evaluate the functional outcome of pups. Pups in arsenic exposed groups weighed less than controls throughout lactation and weaning. Body weight of 10, 50 and 100 mg/L arsenic exposed groups decreased significantly on PND 42, 16 and 12, respectively. Physical development (pinna unfolding, fur appearance, incisor eruption, or eye opening) in pups displayed no significant differences between control and arsenic treated groups. The number of incidences within the 100 mg/L arsenic treated group, in tail hung, auditory startle and visual placing showed significant decrease compared to the control group (p < 0.05). In square water maze test, the trained numbers to finish the trials successfully in 50 and 100 mg/L arsenic exposed groups increased remarkably compared to control group, and there was a dose-related increase (p < 0.01) observed. Taken together, these data show that exposure of inorganic arsenite to pregnant dams and offspring pups at levels up to 100 mg/L in drinking water may affect their learning and memory functions and neuromotor reflex.

Keywords: Rat; Sodium arsenite; Neurobehavior; Development toxicity; Drinking water

Time course of arsenic species in the brain and liver of mice after oral administration of arsenate by Amida Juárez-Reyes; María E. Jiménez-Capdeville; Juan M. Delgado; Deogracias Ortiz-Pérez (pp. 557-563).

The understanding of the biomethylation process of arsenic is essential to uncover the mechanisms of arsenic toxicity. This work analyzes the time course of arsenic species in the brain and liver of adult mice, after a single oral administration of three arsenate doses [2.5, 5.0 and 10 mg As(V)/kg]. Quantification of arsenic species was performed by means of liquid chromatography coupled to atomic fluorescence 2, 5, 8, 12 and 24 h after administration. The results show that 2 h after arsenate administration inorganic arsenic arrives to the liver and its concentration diminishes gradually until becoming non-detectable at 12 h. Arsenic takes longer to appear in the brain and it is present only as dimethyl arsinic acid. Since arsenic concentration decreases in liver while it increases in the brain, this suggests that the arsenic metabolite reaches the brain after formation in the liver. Importantly, the fact that dimethyl arsinic acid is no longer present after 24 h suggests the existence of a mechanism to clear this metabolite from brain tissue.

Keywords: Inorganic arsenic; Biomethylation; Methylated arsenic; Central nervous system; Arsenic metabolism

A comparison of the effect of lead nitrate on rat liver chromatin, DNA and histone proteins in solution by Azra Rabbani-Chadegani; Sayeh Abdosamadi; Nesa Fani; Shayesteh Mohammadian (pp. 565-570).

Although lead is widely recognized as a toxic substance in the environment and directly damage DNA, no studies are available on lead interaction with chromatin and histone proteins. In this work, we have examined the effect of lead nitrate on EDTA-soluble chromatin (SE chromatin), DNA and histones in solution using absorption and fluorescence spectroscopy, thermal denaturation and gel electrophoresis techniques. The results demonstrate that lead nitrate binds with higher affinity to chromatin than to DNA and produces an insoluble complex as monitored at 400 nm. Binding of lead to DNA decreases its Tm, increases its fluorescence intensity and exhibits hypochromicity at 210 nm which reveal that both DNA bases and the backbone participate in the lead–DNA interaction. Lead also binds strongly to histone proteins in the absence of DNA. The results suggest that although lead destabilizes DNA structure, in the chromatin, the binding of lead introduces some sort of compaction and aggregation, and the histone proteins play a key role in this aspect. This chromatin condensation, upon lead exposure, in turn may decrease fidelity of DNA, and inhibits DNA and RNA synthesis, the process that introduces lead toxicity at the chromatin level.

Keywords: Lead; Chromatin; Histones; Metals

Inhibition of rat hepatic CYP2E1 by quinacrine: molecular modeling investigation and effects on 4-(methyl nitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced mutagenicity by Petros Nikolaos Karamanakos; D. T. P. Trafalis; G. D. Geromichalos; P. Pappas; P. Harkitis; M. Konstandi; M. Marselos (pp. 571-580).

Increased activity of CYP2E1 has been associated with increased risk of chemically-mediated cancers, through enhanced activation of a variety of procarcinogens. In this context, inhibition of CYP2E1 is potentially of significance in xenobiotic toxicity. The aim of the present study was to test the hypothesis that quinacrine inhibits hepatic CYP2E1. For this purpose, disulfiram (75 mg/kg i.p) as an inhibitor and isoniazid (100 mg/kg i.p) as an inducer of CYP2E1, as well as quinacrine (50 mg/kg i.p) were administered to Wistar rats and the hepatic activity of CYP2E1 was measured. The expression of CYP2E1 was further assessed by Western blot analysis. As expected, disulfiram inhibited, while isoniazid induced the activity and expression of the enzyme. Interestingly, treatment with quinacrine resulted in a significant decrease of CYP2E1 activity and expression. To investigate any similarities in the inhibition of CYP2E1 by quinacrine and disulfiram, molecular modeling techniques were adopted and revealed that quinacrine molecule anchors inside the same binding pocket of the protein where disulfiram is also attached. Finally, as assessed by the sister chromatid exchanges (SCE) assay, quinacrine was demonstrated to reduce the mutagenic effects of the tobacco-specific N-nitrosamine 4-(methyl nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which is known to be converted to active mutagen in the liver principally through CYP2E1. We suggest that these antimutagenic effects of quinacrine could be possibly attributed, at least in part, to its ability to block the bioactivation of NNK, mainly by the inhibition of CYP2E1. Our results, even preliminary, indicate that quinacrine as an inhibitor of CYP2E1 might be protective against chemically-induced toxicities such as NNK-induced mutagenicity.

Keywords: CYP2E1; Inhibition; Quinacrine; NNK; Mutagenicity; Molecular modeling

Drug metabolizing enzyme expression in rat choroid plexus: effects of in vivo xenobiotics treatment by Daniela Gradinaru; Anne-Laure Minn; Yves Artur; Alain Minn; Jean-Marie Heydel (pp. 581-586).

The presence of drug metabolizing enzymes in extrahepatic tissues such as the choroid plexus (CP) suggests that the CP, like the blood–brain barrier, affords a metabolic protection to the brain against xenobiotics. The CP, which is the principal site of formation of the cerebrospinal fluid (CSF), controls the exchange of many endogenous compounds and exogenous molecules between brain tissue and CSF. We present the changes in mRNA expression and enzymatic activities of UDP-glucuronosyltransferase, UGT1A6 isoform and NADPH-cytochrome P450 reductase, after in vitro treatment with xenobiotic molecules known to act in the liver as inducers or inhibitors of these drug metabolizing enzymes. Five study groups of male Sprague–Dawley rats were treated separately with 3-methylcholantrene (3-MC), phenobarbital (PB), dexamethasone (DEX), cyclosporine (CsA) or paraquat (PQ). Choroidal 1-naphthol glucuronidation activities were significantly induced by 3-MC and PQ administration (354 ± 85 and 257 ± 49 vs. 115 ± 24 nmol/h per mg protein, in control group), whereas the other molecules were without effect. Accordingly, UGT1A6 mRNA expression, measured by RT-PCR, was 2.3-fold higher after 3-MC treatment and 2.1-fold higher after PQ administration. By contrast, reductase activities and mRNA expression remained unchanged in the isolated choroids plexus in these experimental conditions. We present for the first time evidences that the choroids plexus express transcripts for both UGT1A6 and NADPH-cytochrome P450 reductase, and their mRNA expression can be differently regulated by exogenous factors. These results emphasize that xenobiotics could modulate the biotransformation of exogenous and/or endogenous compounds in the choroids plexus, and underline the role of UGTs in the maintenance of brain homeostasis.

Keywords: Choroid plexus; Drug metabolizing enzymes; Glucuronidation; Paraquat

Alterations in neurofilaments content and calpains activity of sciatic nerve of carbon disulfide-treated rats by Fuyong Song; Cuili Zhang; Qingshan Wang; Tao Zeng; Keqin Xie (pp. 587-594).

Chronic exposure to carbon disulfide (CS₂) can induce polyneuropathy in occupational worker and experimental animals, but underlying mechanism for CS₂ neurotoxicity is currently unknown. In the present study, male Wistar rats were randomly divided into two experimental groups and one control group. The rats in two experimental groups were treated with CS₂ by gavage at dosages of 300 and 500 mg/kg per day, respectively, five times per week for 12 weeks. The contents of neurofilament triplet proteins (NF-H, NF-M, NF-L) and two calpain isoforms (m-calpain and u-calpain) in sciatic nerves were determined by immunoblotting. In the meantime, the mRNA levels of NF-H, NF-M and NF-L in spinal cords were quantified by reverse transcriptase-polymerase chain reaction, and the total activity of calpains in sciatic nerves was measured by fluorescence assay. Results showed that the contents of NF-M and NF-L in CS₂-treated rats sciatic nerves increased significantly except NF-M in low dose group. The contents and activity of m-calpain and u-calpain in sciatic nerve also demonstrated a significant elevation. Furthermore, the levels of mRNA expression of NFH, NFM and NFL genes were up-regulated consistently in spinal cords of treated rats. These findings suggested that CS₂ intoxication was associated with the disruption of neurofilaments homeostasis and activiation of calpains in rat sciatic nerves, which might be involved in the development of CS₂-induced peripheral neuropathy.

Keywords: Carbon disulfide; Calpain; Distal axonopathy; Neurofilament

Uranium induces apoptosis in lung epithelial cells by Adaikkappan Periyakaruppan; Shubhashish Sarkar; Prabakaran Ravichandran; Bindu Sadanandan; Chidananda S. Sharma; Vani Ramesh; Joseph C. Hall; Renard Thomas; Bobby L. Wilson; Govindarajan T. Ramesh (pp. 595-600).

Uranium is a naturally occurring radioactive material present everywhere in the environment. It is toxic because of its chemical or radioactive properties. Uranium enters environment mainly from mines and industry and cause threat to human health by accumulating in lungs as a result of inhalation. In our previous study, we have shown the effectiveness of antioxidant system response to the oxidative stress induced by uranyl acetate (UA) in rat lung epithelial (LE) cells. As part of our continuing studies; here, we investigated the mechanism underlying when LE cells are exposed to different concentration of UA. Oxidative stress may lead to apoptotic signaling pathways. LE cells treated with 0.25, 0.5 and 1 mM of UA results in dose and time-dependent increase in activity of both caspases-3 and -8. Increase in the concentration of cytochrome-c oxidase in cytosol was seen in LE cells treated with 1 mM UA as a result of mitochondria membrane permeability. The cytochrome-c leakage may trigger the apoptotic pathway. TUNEL assay performed in LE cells treated with 1 mM of UA showed significant incorporation of dNTPs in the nucleus after 24 h. In the presence of the caspase inhibitors, we observed the significant decrease in the activity of caspases-8 and -3 in 0.5 and 1 mM UA-treated LE cells.

Keywords: Uranium; Apoptosis; Cytochrome-c; Caspase

Lactational coumestrol exposure increases ovarian apoptosis in adult rats by Hyun-Ju Moon; Ji Hyun Seok; Soon Sun Kim; Gyu Seek Rhee; Rhee Da Lee; Jun Young Yang; Soo Yeong Chae; Seung Hee Kim; Ji Young Kim; Jin-Yong Chung; Jong-Min Kim; Soo Youn Chung (pp. 601-608).

This study is the first to examine the increased apoptosis in the adult rat ovary after lactational exposure to coumestrol (COU), a potent phytoestrogen. Lactating dams were gavaged at doses of 0.01, 0.1, 1, and 10 mg/kg COU during the lactation period and the reproductive effects of female pups were investigated in young adults. Rats were sacrificed at postnatal days (PND) 81–84. Ovarian weights were reduced significantly at 0.1 and 1.0 mg/kg COU. The reduction in the ovarian weight occurred in parallel with an increase in the apoptosis at PND 135–140. A marked dose-dependent increase in the expressions of active caspase-3 and -7 was observed in ovarian granulosa cells. Immunostaining for active caspase-3 and the TUNEL staining of apoptotic cells were also increased in ovaries exposed to COU in a dose-dependent manner. These results suggest new sights into the effect of lactational exposure to COU on the female reproductive health.

Keywords: Ovarian apoptosis; Coumestrol; Lactational exposure; Caspase-3

Protective effects of curcumin against gamma radiation-induced ileal mucosal damage by Meryem Akpolat; Mehmet Kanter; Mustafa Cem Uzal (pp. 609-617).

The major objective of this study was to test curcumin as a potential radioprotectant for the ileum goblet cells of the rat. Wistar albino rats were used in the study. Group A was the control group and group B was the single dose radiation group. Group C was the two dose radiation group (4 days interval). The rats in groups D and E were given a daily dose of 100 mg/kg of curcumin for 14 and 18 days, respectively. During the curcumin administration period, the rats in group D were exposed to abdominal area gamma (γ)-ray dose of 5 Gy on the 10th day and group E was exposed to same dose radiation on the 10th and 14th day. Irradiation and treatment groups were decapitated on the 4th day after exposure to single or two-dose irradiation and ileum tissues were removed for light and electron microscopic investigation. Single or two dose 5 Gy γ-irradiation caused a marked intestinal mucosal injury in rats on the 4th day. Radiation produced increases in the number of goblet cells. Curcumin appears to have protective effects against radiation-induced damage, suggesting that clinical transfer is feasible.

Keywords: Radioprotection; Curcumin; Ileum; Goblet cell; Morphometry; Rat

Dual-label time-resolved fluoroimmunoassay for simultaneous detection of aflatoxin B1 and ochratoxin A by Biao Huang; Hualong Xiao; Jue Zhang; Lianfen Zhang; Hailin Yang; Yi Zhang; Jian Jin (pp. 619-624).

A dual-label time-resolved fluoroimmunoassay (TRFIA) for simultaneous quantification of aflatoxin B1 (AFB1) and ochratoxin A (OTA) is described. For this, microtitration wells were coated with AFB1-horse radish peroxidase (HRP) and OTA–bovine serum albumin. The standards and samples were loaded on the coated plates, and diluted antibodies and Eu³⁺-

Keywords: and Sm³⁺-labeled IgG were then added. Our results showed that the sensitivity of TRFIA for AFB1 was 0.02 μg/L (range 0.02–100 μg/L). The intra- and inter-batch coefficient of variation (CV) was 3.2 and 7.3%, respectively, and the average recovery rate was 88.1%. On the other hand, the sensitivity of OTA was 0.05 μg/L (range 0.05–50 μg/L), the intra- and inter-batch CV was 2.9 and 7.9%, respectively, and the average recovery rate was 89.9%. In the AFB1/OTA–TRFIA, AFB1 and OTA did not mutually interfere. The correlation coefficients between the dual-label AFB1/OTA–TRFIA and the single-label AFB1–TRFIA or OTA–TRFIA were 0.972 and 0.981, respectively, indicating that the results were consistent. Our study suggests that AFB1/OTA–TRFIA allows the simultaneous detection of AFB1 and OTA; is a simple, fast, and economic method for screening large quantities of samples, and has good prospects of application.

Statistical evaluation of the in vivo micronucleus assay by Ludwig A. Hothorn; Daniel Gerhard (pp. 625-634).

The statistical evaluation of the in vivo micronucleus assay is focused on multiple contrast tests for comparisons versus the negative control for count data taking the between-animals variability into account. For a possible claim the compound is not genotoxic in the micronucleus assay a proof of safety approach is proposed. For these statistical approaches user-friendly software is free available.

Keywords: In vivo micronucleus assay; Statistics; Software

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Archives of Toxicology (v.83, #6)