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Archives of Toxicology (v.82, #9)

Aryl hydrocarbon receptor-mediated regulation of the human estrogen and bile acid UDP-glucuronosyltransferase 1A3 gene by Tim O. Lankisch; Tracey C. Gillman; Thomas J. Erichsen; Ursula Ehmer; Sandra Kalthoff; Nicole Freiberg; Peter A. Munzel; Michael P. Manns; Christian P. Strassburg (pp. 573-582).

UDP-glucuronosyltransferases contribute to the detoxification of drugs by forming water soluble β-d-glucopyranosiduronic acids. The human UGT1A3 protein catalyzes the glucuronidation of estrogens, bile acids and xenobiotics including non-steroidal anti-inflammatory drugs and lipid lowering drugs. Regulation of UGT1A3 by xenobiotic response elements is likely, but the responsible elements are yet uncharacterized. In addition, genetic promoter variants may affect UGT1A3 regulation and potential induction by xenobiotics. The UGT1A3 promoter was analyzed by mutagenesis, reporter gene, and mobility shift analyses. Three hundred and eighty-nine blood donors were genotyped for promoter single nucleotide polymorphisms (SNPs) showing an allelic frequency of 42% of variants at −66 (T to C) and −204 (A to G). A xenobiotic response element regulating aryl hydrocarbon receptor (AhR)-mediated UGT1A3 transcription was identified and characterized. UGT1A3 transcription was reduced in the presence of promoter SNPs. These data demonstrate xenobiotic induced regulation of the UGT1A3 gene by the AhR, which shows genetic variability.

Keywords: UDP glucuronosyltransferase; Transcriptional regulation; Dioxin; Single nucleotide polymorphism; UGT1A3 ; Xenobiotic response element; Aryl hydrocarbon receptor

In vivo effects of chronic contamination with 137 cesium on testicular and adrenal steroidogenesis by Elise Grignard; Yann Guéguen; Stéphane Grison; Jean-Marc A. Lobaccaro; Patrick Gourmelon; Maâmar Souidi (pp. 583-589).

More than 20 years after Chernobyl nuclear power plant explosion, radionuclids are still mainly bound to the organic soil layers. The radiation exposure is dominated by the external exposure to gamma-radiation following the decay of ¹³⁷Cs and by soil-to-plant-to-human transfer of ¹³⁷Cs into the food chain. Because of this persistence of contamination with ¹³⁷Cs, questions regarding public health for people living in contaminated areas were raised. We investigated the biological effects of chronic exposure to ¹³⁷Cs on testicular and adrenal steroidogenesis metabolisms in rat. Animals were exposed to radionuclide in their drinking water for 9 months at a dose of 6,500 Bq/l (610 Bq/kg/day). Cesium contamination decreases the level of circulating 17β-estradiol, and increases corticosterone level. In testis, several nuclear receptors messenger expression is disrupted; levels of mRNA encoding Liver X receptor α (LXRα) and LXRβ are increased, whereas farnesoid X receptor mRNA presents a lower level. Adrenal metabolism presents a paradoxical decrease in cyp11a1 gene expression. In conclusion, our results show for the first time molecular and hormonal modifications in testicular and adrenal steroidogenic metabolism, induced by chronic contamination with low doses of ¹³⁷Cs.

Keywords: Steroidogenesis; Testis; Adrenal; Cesium; Chronic contamination

Bio-distribution study of 1,2-diethylbenzene and its main metabolites by whole-body autoradiography and tissue homogenates by Jean-Paul Payan; Stephane Binet; Dominique Beydon; Elisabeth Ferrari (pp. 591-600).

The bio-distribution of the neurotoxic 1,2-diethylbenzene (1,2-DEB) was studied in male Sprague-Dawley rats after intravenous administration of [¹⁴C] 1,2-DEB (1 mg kg⁻¹). The highest concentrations of [¹⁴C] non-volatile metabolites, determined by whole-body auto-radiography, were in the nasal cavity, ethmoid turbinates and in kidney. Whatever the time after dosing, the [¹⁴C] concentrations in the cerebrum, cerebellum, spinal cord and lung were lower than those in the blood. In contrast, after killing of batch of administered rats, the [¹⁴C] concentrations in the brain homogenates were higher than in plasma for 5–15 min. In addition, the [¹⁴C] concentrations in the lung were higher than in the plasma for 24 h post-dose. Moreover, the concentrations of unchanged 1,2-DEB and one of its metabolites, 1-(2′-ethylphenyl)ethanol (1,2-EPE) in the brain, were higher than in the plasma until 1 h post-dose. The concentrations of 1,2-DEB in the blood cells were tenfold higher than in the plasma. The clearance of unchanged 1,2-DEB in the whole blood and in the blood cells was 6.4 and 3.9 ml min⁻¹, respectively. The apparent half-life of unchanged 1,2-DEB in plasma is very fast (5 min) which suggests a quick distribution and/or metabolism in liver and/or other tissues such as the lung. In conclusion, unchanged 1,2-DEB has a high affinity for the brain and blood cells and its concentrations in plasma and brain decreased rapidly with time.

Keywords: 1,2-Diethylbenzene; Distribution; Autoradiography; Toxicokinetics; Rat

Hydrophobic interaction of organic chemicals with microtubule assembly in vitro by Thomas Stoiber; Eberhard Unger; Susanne B. Dorn; Gisela H. Degen; Hermann M. Bolt (pp. 601-606).

A recent concept connecting the lipophilicity of organic chemicals with their genotoxicity on a chromosomal level implies that the lipophilic character of organic chemicals determines a certain background of chromosomal genotoxicity that can be addressed as “non-specific”. This is opposed to compounds with more “specific” modes of action. Such mechanisms influence the processes of karyokinesis and cytokinesis. A critical partial process for the chromosomal segregation is the dynamics of assembly and disassembly of microtubules. To broaden the present database for such interactions, chemicals were selected based on their lipophilicity (log P between −1.5 and +1.0) and on hints from the literature pointing to possibilities of interaction with the tubulin–microtubule system. Thus, acetamide, acrylamide, methylmethane sulfonate, acetonitrile, acrylonitrile and cyclohexanone were assessed as to their potencies to influence the dynamic processes of microtubule assembly and disassembly in a cell-free system in vitro. These compounds covered a range of log P between −1.5 and 1.0, complementary to compounds investigated earlier. The entire body of data supports the general concept that hydrophobic interactions are connected with non-specific processes, which contribute to a background genotoxicity on a chromosomal level. It also points to the dynamics of microtubule assembly and disassembly as a decisive partial process involved.

Keywords: Organic compounds; Hydrophobic interactions; Genotoxicity; Tubulin interaction; Acetamide; Acrylamide; Methylmethane sulfonate; Acetonitrile; Cyclohexanone; Benzonitrile; Nitrobenzene

Mechanisms of the ifosfamide-induced inhibition of endocytosis in the rat proximal kidney tubule by Zeinab Yaseen; Christian Michoudet; Gabriel Baverel; Laurence Dubourg (pp. 607-614).

The Fanconi syndrome is a common side effect of the chemotherapeutic agent ifosfamide. Current evidences suggest that chloroacetaldehyde (CAA), one of the main metabolites of ifosfamide activation, contributes to its nephrotoxicity. However, the pathophysiology of CAA-induced Fanconi syndrome is not fully understood. The present work examined the adverse effects of CAA on precision-cut rat renal cortical slices, which allowed studying the toxic effect of CAA on proximal endocytosis. We demonstrated that clinically relevant concentrations of CAA (≤200 μM) are able to inhibit the uptake of horseradish peroxidase, a marker of proximal tubular cell endocytosis in renal tubular proximal cells. CAA ≥75 μM has adverse effects, both on viability parameters and on energy metabolism, as shown by the great decrease in total glutathione and ATP levels. In addition, the V-ATPase, which plays a crucial role in intracellular vesicle trafficking, was inhibited by 100 μM of CAA. By contrast, the slight decrease in Na–K–ATPase activity observed for CAA≥ 125 μM (maximum inhibition: 33%) could not totally explain the inhibition of the reabsorption processes. In conclusion, the addition of the two main adverse effects of CAA (decrease in ATP levels and inhibition of the V-ATPase) could explain the inhibition of endocytosis and the Fanconi syndrome observed during ifosfamide treatments.

Keywords: Chloroacetaldehyde; Ifosfamide; V-ATPase; Nephrotoxicity; Proximal tubule

Cell protection induced by beta-sitosterol: inhibition of genotoxic damage, stimulation of lymphocyte production, and determination of its antioxidant capacity by R. Paniagua-Pérez; E. Madrigal-Bujaidar; S. Reyes-Cadena; I. Álvarez-González; L. Sánchez-Chapul; J. Pérez-Gallaga; N. Hernández; G. Flores-Mondragón; O. Velasco (pp. 615-622).

Beta-sitosterol (BS) is a compound that has shown various activities potentially useful for human health. In the present study, we determined its antigenotoxic capacity and lymphocyte induction potential in mouse as well as its capacity to trap free radicals in vitro. BS, in doses from 200 to 1,000 mg/kg, was able to significantly reduce the frequency of sister chromatid exchanges induced by 10 mg/kg of doxorubicin (DX) in bone marrow cells. The same range of BS doses also gave rise to a strong reduction in the rate of micronucleated, polychromatic erythrocytes induced by DX. In addition, we determined an increase in the production of lymphocytes in mice administered with BS. By means of the DPPH assay, the compound was shown to trap free radicals in a concentration dependent manner as high as 78.12% using 250 μg/ml. Our research established three relevant biological activities of BS which show its potential as a chemopreventive agent.

Keywords: Beta-sitosterol; Doxorubicin; Antigenotoxicity; Antioxidant

Promotion of hepatocarcinogenesis in humans and animal models by Christoph Köhle; Michael Schwarz; Karl Walter Bock (pp. 623-631).

Risk assessment based on rodent carcinogenicity data depends on the assumption of similarity between rodents and humans. While this assumption is conceivable in the case of genotoxic initiating carcinogens, considerable species differences have been observed with nongenotoxic tumor promoters. This heterogeneous group of agents increases the probability of cancer by stimulating selection and clonal expansion of cells transformed during tumor initiation. Since tumor promoters differentially affect normal tissue and preneoplastic cell clones, their action cannot be discussed without knowledge of persistent genomic and epigenetic alterations occurring during initiation and formation of preneoplastic cells. Chemical carcinogenesis, and in particular, tumor promotion, is known to be tissue specific. We focus on hepatocarcinogenesis in humans and in animal models and emphasize two different modes of action: (1) chronic cytotoxicity leading to promotion of liver carcinogenesis in both humans and animal models; (2) sustained activation of orphan receptors such as CAR, PPARα and Ah receptor leading to promotion of rodent but probably not human hepatocarcinogenesis. Further studies on the different modes of action may help to avoid overestimation of the risk of liver tumor promotion.

Keywords: Hepatocarcinogenesis; Tumor promoters; Ethanol; Phenobarbital; TCDD

Genetic polymorphisms of cytochrome P450 CYP1A1 (*2A) and microsomal epoxide hydrolase gene, interactions with tobacco-users, and susceptibility to bladder cancer: a study from North India by Daya Shankar Srivastava; Anil Mandhani; Rama Devi Mittal (pp. 633-639).

The role of low penetrance genes and environmental factors in the etiology of bladder cancer (CaB) is unclear, but may involve genetic and environmental factors. Most environmental pro-carcinogens require metabolic activation by phase I enzymes (CYP450s), However, phase II enzyme (i.e., microsomal epoxide hydrolase: mEH) is mainly involved in the detoxification of wide variety of endogenous or exogenous carcinogens. Genetic differences in CYP1A1 gene and the mEH gene polymorphisms have been reported to be associated with susceptibility to various cancers. In our case–control study, we assess whether Msp1 polymorphism of CYP1A1 (CYP1A1*2A), and His₁₁₃ in exon 3 and Arg₁₃₉ in exon 4 of the mEH susceptibility genotypes, tobacco-use and age factors contribute to bladder cancer risk among Indians. A case–control study was conducted in 106 bladder cancer (CaB) patients and 160 age matched controls from similar ethnic background. The CYP1A1*2A and mEH genotypes were determined by polymerase chain reaction/restriction fragment length polymorphism method from DNA extracted from peripheral blood samples. Binary logistic regression model was used for assessing differences in genotype prevalence between patients and the controls. The Arlequin software package was used to compute haplotype frequencies. We observed non-significant association in T/C polymorphism of the CYP1A1 gene (CYP1A1*2A); however, the exon 3 His genotype of the mEH gene polymorphism alone (odds ratio = 2.67, P = 0.001) or in combination with tobacco-users were significantly associated with the risk of bladder cancer. No associations were observed with stage or grade of bladder tumor with these genotypes. In conclusion, our study demonstrated that exon 3 His genotype of the mEH are more prone to the risk of sporadic bladder cancer in North India.

Keywords: Microsomal epoxide hydrolase; Cytochrome P450 1A1; Genetic polymorphisms; Bladder cancer (CaB); Polymerase chain reaction/restriction fragment length polymorphism

Possible involvement of oxidative stress in fenofibrate-induced hepatocarcinogenesis in rats by Jihei Nishimura; Yasuaki Dewa; Toshiya Okamura; Masako Muguruma; Meilan Jin; Yukie Saegusa; Takashi Umemura; Kunitoshi Mitsumori (pp. 641-654).

To clarify whether oxidative stress is involved in the development of hepatocellular preneoplastic foci induced by fenofibrate (FF), a peroxisome proliferator-activated receptor alpha agonist, male F344/N rats were fed a diet containing 6,000, 3,000, or 0 ppm of FF for 13 weeks after N-diethylnitrosamine initiation. Two-third partial hepatectomy was performed 1 week after the FF treatment. Histopathologically, the number of hepatocellular altered foci significantly increased in the FF-treated groups with a concomitant increase in the number of hepatocytes positive for anti-Ki-67 antibody, but the number and area of glutathione S-transferase placental form (GST-P)-positive foci decreased in these groups, as compared to those in the controls. Microarray analysis or quantitative real-time reverse transcription-polymerase chine reaction demonstrated the significant up-regulations of Aco and Cyp4a1 (genes related to lipid metabolism); Gpx2, Yc2, Cat, Cyp2b15, and Ugt1a6 (metabolic oxidative stress-related genes); Apex1, Mgmt, Xrcc5, Nbn, and Gadd45a (DNA repair-related genes); and Ccnd1 (cell cycle-related genes) in the FF-treated groups, and the significant down-regulations of Cyp1a2, Gsta2, Gstm2, and Gstm3 (phase I or II metabolism-related genes); Mlh1 and Top1 (DNA repair-related genes); and Cdkn1a, Cdkn1b, Chek2, and Gadd45b (cell cycle/apoptosis-related genes) in these rats. FF-treatment increased the activity of enzymes such as carnitine acetyltransferase, carnitine palmitoyltransferase, fatty acyl-CoA oxidizing system, and catalase in the liver, but not superoxide dismutase in the liver. In addition, 8-OHdG level in liver DNA, lipofuscin deposition in hepatocytes, and in vitro reactive oxygen species production in microsomes significantly increased due to FF treatment. These results suggest that oxidative stress is involved in the development of FF-induced hepatocellular preneoplastic foci in rats.

Keywords: Peroxisome proliferator; PPARα; Fenofibrate; Oxidative stress; DNA damage; Hepatocarcinogenesis

Diphenyl diselenide supplementation delays the development of N-nitroso-N-methylurea-induced mammary tumors by Nilda Berenice de Vargas Barbosa; Cristina Wayne Nogueira; Temenouga N. Guecheva; Maria de Lourdes Bellinaso; João Batista Teixeira Rocha (pp. 655-663).

The effect of dietary diphenyl diselenide (1 ppm) on N-nitroso-N-methylurea (NMU)-induced mammary carcinogenesis was examined in female Wistar rats. Beginning at 5 weeks of age, the animals were fed with either control or diphenyl-diselenide-supplied diets until the end of the study (210 days). At 50 days of age, mammary tumor was induced by the administration of three doses of NMU (50 mg/kg body wt, intraperitoneally) once a week for 3 weeks. In experimental trials, latency to tumor onset was extended in rats fed with diet supplemented with diphenyl diselenide (P < 0.05). The incidence and frequency of tumors were significantly small in animals supplemented with diphenyl diselenide. However, the multiplicity of tumors was not altered by dietary diphenyl diselenide. Diphenyl diselenide supplementation also restored superoxide dismutase (SOD) activity and vitamin C levels altered in the NMU group (P < 0.05). Our results suggest that diphenyl diselenide can be considered a chemopreventive agent, even when supplemented at a relatively low concentration.

Keywords: Mammary tumors; Chemoprophylaxis; Selenium; N-nitroso-N-methylurea

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Archives of Toxicology (v.82, #9)