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Новые публикации по токсикологии и смежным дисциплинам Phenobarbital, b-Naphthoflavone, Clofibrate, and Pregnenolone-16a-Carbonitrile Do Not Affect Hepatic Thyroid Hormone UDP-Glucuronosyl Transferase Activity, and Thyroid Gland Function in Mice Catherine Viollon-Abadie, Dominique Lassere, Eric Debruyne, Laurence Nicod, Neil Carmichael, Lysiane Richert The effects of representative liver enzyme inducers such as clofibrate (CLO), phenobarbital (PB), regnenolone-16a-carbonitrile (PCN), and b-naphthoflavone (NF) on hepatic microsomal thyroxin (T4)- UDP-glucuronosyl tranferase (UGT) and triiodothyronine (T3)- UGT activities and thyroid function were evaluated in OF-1 male mice after a 14-day po administration. CLO, PB, and PCN induced histological liver hypertrophy, increases in liver weights, in microsomal protein and cytochrome P450 contents as well as increases in specific UGT activities. Despite this, no significant changes in T4-UGT and T3-UGT activities occurred after treatment by any of these compounds. Furthermore, no significant changes in serum T4 and T3 levels were observed and thyroid histology was not affected. NF treatment induced microvacuolation of hepatocytes but did not affect any of the other tested parameters. The results show that, in contrast to the widely described effects in rats, liver enzyme inducers do not affect hepatic thyroid hormone metabolism and thyroid function in mice, suggesting that this species should be less sensitive to thyroid tumor promotion by hepatic microsomal enzyme inducers than rats. Copyright 1999 Academic Press. Toxicology and Applied Pharmacology, v 155, n 1, February 15, 1999, p1-12 (ID taap.1998.8558) Structure-Dependent Induction of CYP1A by Polychlorinated Biphenyls in Hepatocytes of Cynomolgus Monkeys (Macaca fascicularis) Aafje S. A. M. van der Burght, Peter J. Clijsters, G. Jean Horbach, Patrik L. Andersson, Mats Tysklind, Martin van den Berg Toxicology and Applied Pharmacology, v 155, n 1, February 15, 1999, p13-23 (ID taap.1998.8606) Inhibition by Lead of Production and Secretion of Transthyretin in the Choroid Plexus: Its Relation to Thyroxine Transport at Blood-CSF Barrier Wei Zheng, William S. Blaner, Qiuqu Zhao Toxicology and Applied Pharmacology, v 155, n 1, February 15, 1999, p24-31 (ID taap.1998.8611) Phenobarbital Induction of CYP2B1/2 in Primary Hepatocytes: Endocrine Regulation and Evidence for a Single Pathway for Multiple Inducers Leonardo G. Ganem, Eric Trottier, Alan Anderson, Colin R. Jefcoate Toxicology and Applied Pharmacology, v 155, n 1, February 15, 1999, p 32-42 (ID taap.1998.8599) Kinetic Evidence for Different Mechanisms of Acetylcholinesterase Inhibition by (1R)- and (1S)-Stereoisomers of Isomalathion Suree Jianmongkol, Brian R. Marable, Clifford E. Berkman, Todd T. Talley, Charles M. Thompson, Rudy J. Richardson Toxicology and Applied Pharmacology, v 155, n 1, February 15, 1999, p43-53 (ID taap.1998.8608) Suppression of Calcium Oscillation by Tri-n-Butyltin Chloride in Cultured Rat Hepatocytes Toru Kawanishi, Hiroki Asoh, Takashi Kato, Chikako Uneyama, Kazuhiro Toyoda, Reiko Teshima, Hideharu Ikebuchi, Hisayuki Ohata, Kazutaka Momose, Takao Hayakawa, Michihito Takahashi Toxicology and Applied Pharmacology, v 155, n 1, February 15, 1999, p54-61 (ID taap.1998.8600) Adverse Reproductive Outcomes in the Transgenic Ah Receptor-Deficient Mouse Barbara D. Abbott, Judith E. Schmid, Jeff A. Pitt, Angela R. Buckalew, Carmen R. Wood, Gary A. Held, Janet J. Diliberto The aryl hydrocarbon receptor (AHR) is a transcriptional regulatory protein that binds to upstream DNA response elements of target genes. Activation of the AHR by binding of ligands such as polyhalogenated dioxins, furans, and PCBs is associated with a wide range of adverse biological outcomes, including cancer, immune deficiencies, embryo/fetotoxicity, and reproductive toxicity. Investigations of the diverse biological responses mediated by the AHR led to production of a transgenic mouse in which the gene coding for the AhR was inactivated. AHR-deficient mice were fertile and at maturity exhibited immune system impairment and hepatic fibrosis. Our laboratory received several of these homozygous knockout (-/-) mice and mated them with wild-type (+/+) C57BL/6N mice to generate large numbers of heterozygotes (+/-). The -/- males were then mated with a total of 45 heterozygous +/- females. Offspring of these matings were genotyped and mated in all genotypic combinations. Although male and female -/- adults were fertile, the -/- females had difficulty maintaining conceptuses during pregnancy, surviving pregnancy and lactation, and rearing pups to weaning. Only 46% of the 39 pregnant -/- females successfully raised pups to weaning. The -/- pups showed poor survival during lactation (average death rate per litter was 16%) and after weaning (26.5% of the 230 weaned -/- pups died within 2 weeks). Only 39% of the implantations in uteri of -/- dams resulted in offspring surviving to Postnatal Day 45. Across all litters the sex ratios and genotypic frequencies were comparable to expected values. Reproductive success was adversely affected in Ahr-null females and conceptuses. Additional study is needed to reveal the etiology of these effects. Copyright 1999 Academic Press. Toxicology and Applied Pharmacology, v 155, n 1, February 15, 1999, p62-70 (ID taap.1998.8601) The AH Receptor and a Novel Gene Determine Acute Toxic Responses to TCDD: Segregation of the Resistant Alleles to Different Rat Lines Jouni T. Tuomisto, Matti Viluksela, Raimo Pohjanvirta, Jouko Tuomisto 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), the most toxic congener of dioxins, exhibits wide sensitivity differences between a sensitive Long-Evans (L-E) rat and a resistant Han/Wistar (H/W) rat. The sensitivity is determined probably by two autosomal genes and it is highly end point dependent. The difference is more than 1000-fold for acute toxicity and negligible for CYP1A1 induction. The rat strains were recently shown to have differences in the size of AH receptor (AHR), which mediates most effects of TCDD. In the present study, the rat strains were crossed and the resistant alleles of genes determining TCDD sensitivity were segregated to new rat lines. Selection was based on AHR phenotype determined by Western blot and resistance to TCDD lethality. Two genes determining resistance were found: the Ahr and a novel gene designated "B." In homozygous rats, the H/W type Ahrhw allele prevented TCDD lethality up to 2000 µg/kg or more, and the H/W type "Bhw" allele also increased resistance to TCDD lethality but to a lesser extent. Heterozygous rats were only slightly more resistant to acute lethality than the respective sensitive homozygous rats. CYP1A1 induction was similar irrespective of the Ahr and "B" genotypes, but a substantial increase in serum bilirubin seen after low doses in sensitive rats occurred only after large doses in "Bhw/hw" and not at all in Ahrhw/hw rats. In conclusion, the Ahrhw allele is a major determinant of the exceptional resistance of H/W rats to TCDD lethality. There is also an additional gene, whose function remains to be characterized, conferring limited resistance to TCDD toxicity. These two H/W rat-derived alleles are separately expressed in the new rat lines created. Copyright 1999 Academic Press. Toxicology and Applied Pharmacology, v 155, n 1, February 15, 1999, p71-81 (ID taap.1998.8564) Physicochemical Differences in the AH Receptors of the Most TCDD-Susceptible and the Most TCDD-Resistant Rat Strains Raimo Pohjanvirta, Matti Viluksela, Jouni T. Tuomisto, Mikko Unkila, Joanna Karasinska, Monique-Andree Franc, Mary Holowenko, John V. Giannone, Patricia A. Harper, Jouko Tuomisto, Allan B. Okey Toxicology and Applied Pharmacology, v 155, n 1, February 15, 1999, p82-95 (ID taap.1998.8565) Transcriptional Activation of Avian CYP1A4 and CYP1A5 by 2,3,7,8-Tetrachlorodibenzo-p-dioxin: Differences in Gene Expression and Regulation Compared to Mammalian CYP1A1 and CYP1A2 S.S. Mahajan, A.B. Rifkind The toxicity, carcinogenicity, and biochemical effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are dependent upon activation of the Ah receptor, a ligand-activated transcription factor. Ah receptor activation leads to the induction of cytochrome P450 (CYP) 1A enzymes, which include CYP1A1 and 1A2 in mammals and CYP1A4 and 1A5 in chickens. CYP1A induction is a major effect of TCDD exposure although its relationship to TCDD toxicity and carcinogenicity are not understood. In these studies we investigated by nuclear run-on transcription assays along with Northern and Western blotting in chick embryo liver, kidney, and heart whether avian CYP1A4 and 1A5, like mammalian CYP1A1 and 1A2, are transcriptionally induced by TCDD and whether the chick CYP1A enzymes exhibit differences analogous to mammalian CYP1A enzymes in organ expression. We report that CYP1A4 and 1A5, like CYP1A1 and 1A2, are transcriptionally induced by TCDD in liver. However, whereas CYP1A1 is not constitutively expressed in liver, CYP1A2 and both CYP1A4 and 1A5 are constitutively expressed. Further, whereas TCDD induces only CYP1A1 and not CYP1A2 in extrahepatic organs, TCDD induces both CYP1A4 and 1A5 in chick kidney. Also, TCDD induced CYP1A4 but not 1A5 in both myocardium and heart vessels whereas CYP1A1 induction has only been found in endocardium. Further, liver CYP1A4 and 1A5 mRNAs had the same half lives and were both superinduced by cycloheximide, whereas mRNA half lives differ for CYP1A1 and 1A2, and cycloheximide superinduces only CYP1A1. We suggest that there are species differences in the effects of TCDD on CYP1A gene expression, organ distribution, and regulation that are likely to be accompanied by differences in CYP1A function and that this diversity may contribute to the large differences in sensitivity to TCDD among species. Copyright 1999 Academic Press. Toxicology and Applied Pharmacology, v 155, n 1, February 15, 1999, p96-106 (ID taap.1998.8615) Metallothionein Overexpression Supresses Hepatic Hyperplasia Induced by Hepatitis B Surface Antigen Carol J. Quaife, Russell L. Cherne, Terry G. Newcomb, Raj P. Kapur, Richard D. Palmiter Toxicology and Applied Pharmacology, v 155, n 2, March 1, 1999, p107-116 (ID taap.1998.8609) Effects of Cadmium Chloride on the Paracellular Barrier Function of Intestinal Epithelial Cell Lines Erwin Duizer, Andries J. Gilde, Carolien H. M. Versantvoort, John P. Groten In the present study we characterized the functional and structural disruption of the paracellular barrier of intestinal epithelium in vitro in relation to cytotoxicity after apical Cd2+ exposure. For that purpose filter-grown Caco-2 and IEC-18 cells were apically exposed to 5 to 100 µM CdCl2 for 4 or 14 h. It was found that the effects of Cd2+ on the epithelial barrier were concentration- and time-dependent. The first detected effects of Cd2+ in Caco-2 cells after 4 h exposure were a decrease in transepithelial electrical resistance, increased permeabilities of mannitol and PEG-4000, and changes in intercellular localization of ZO-1, occludin, and e-cadherin. The effects were far more pronounced after prolonged exposure. The disruption of the paracellular barrier by 5 to 30 µM Cd2+ was detected without a significant loss of viability of the Caco-2 cells. In the IEC-18 cells, Cd2+ concentrations affecting the barrier (50 and 100 µM) also affected cell viability. In both cell lines the effects on the cell layers continued to develop after removal of extracellular Cd2+. This correlated with the cellular retention of Cd2+, which was high for the 12 h following 4 h accumulation. This study showed that the decreased epithelial barrier function of intestinal epithelial cells is accompanied by tight junction disruption. It is concluded that Cd2+ causes increased paracellular permeability by disruption of junctional function and structure. The initial junctional effects of Cd2+ suggest that Cd2+ increases its own bioavailability by causing disruption of the intestinal paracellular barrier. Copyright 1999 Academic Press. Toxicology and Applied Pharmacology, v 155, n 2, March 1, 1999, p117-126 (ID taap.1998.8589) Time- and Concentration-Dependent Induction of CYP1A1 and CYP1A2 in Precision-Cut Rat Liver Slices Incubated in Dynamic Organ Culture in the Presence of 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Adam T. Drahushuk, Barbara P. McGarrigle, Brian P. Slezak, John J. Stegeman, James R. Olson Toxicology and Applied Pharmacology, v 155, n 2, March 1, 1999, p127-138 (ID taap.1998.8578) Involvement of Germ Cell Apoptosis in the Induction of Testicular Toxicity Following Hydroxyurea Treatment Jae-Ho Shin, Chisato Mori, Kohei Shiota The present study investigated the occurrence of apoptotic cell death in the mouse testis at various intervals following the administration of hydroxyurea (HU). The presence of apoptosis was assessed by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) method and by DNA fragmentation assay using ligation-mediated polymerase chain reaction. Both the incidence of apoptotic cells and the level of DNA fragmentation in the testis increased depending on the HU dose, and they were most apparent at the highest dose (400 mg/kg). The incidence of apoptotic cells in the HU-treated group increased continuously and peaked at 12 h, but then decreased gradually, reaching control levels by 48 h. After HU treatment, TUNEL-positive apoptotic cells increased in the seminiferous epithelium of the tubules, and affected cells were found synchronously in the tubules of animals treated with HU. Spermatogonia and spermatocytes were found to be affected selectively. TUNEL-positive cells were found to be stage-specific and were primarily in stage IV-VI tubules. It has been shown that in vivo HU exposure induced testicular germ cell apoptosis dose dependently in a time- and stage-specific manner, and damaged cells appeared to be eliminated by phagocytosis by neighboring cells. Apoptosis of damaged testicular germ cells is apparently a common response to various testicular toxicants therefore protecting the next generations of germ cells from the damaged cell population. Copyright 1999 Academic Press. Toxicology and Applied Pharmacology, v 155, n 2, March 1, 1999, p139-149 (ID taap.1998.8593) Rapid and Sensitive Reporter Gene Assays for Detection of Antiandrogenic and Estrogenic Effects of Environmental Chemicals Anne Marie Vinggaard, Eva Cecilie Bonefeld Joergensen, John Christian Larsen Reports on increasing incidences in developmental abnormalities of the human male reproductive tract and the recent identifications of environmental chemicals with antiandrogenic activity necessitate the screening of a larger number of compounds in order to get an overview of potential antiandrogenic chemicals present in our environment. Thus, there is a great need for an effective in vitro screening method for (anti)androgenic chemicals. We have developed a rapid, sensitive, and reproducible reporter gene assay for detection of antiandrogenic chemicals. Chinese Hamster Ovary cells were cotransfected with the human androgen receptor expression vector and the mouse mammary tumour virus (MMTV)2-luciferase vector using the new nonliposomal transfection reagent FuGene. Stimulation of the cells for 24 h with the synthetic androgen receptor agonist, R1881 (10 nM), resulted in a 30- to 60-fold induction of luciferase activity. The classical antiandrogenic compounds hydroxy-flutamide, bicalutamide, spironolactone, and cyproterone acetate together with the pesticide(metabolite)s, vinclozolin, p,p'-DDE, and procymidone all potently inhibited the response to 0.1 nM R1881. Compared to the traditional calcium phosphate transfection method, this method has the advantage of being more feasible, as the assay can be scaled down to the microtiter plate format. Furthermore, the transfection reagent is noncytotoxic, allowing its addition together with the test compounds thereby reducing the hands-on laboratory time. This assay is a powerful tool for the efficient and accurate determination and quantification of the effects of antiandrogens on reporter gene transcription. To extend the application of FuGene, the reagent was shown to be superior compared to Lipofectin for transfecting MCF7 human breast cancer cells with an estrogen response element-luciferase vector. Thus, FuGene may prove to be valuable in diverse reporter gene assays involving transient transfections for screening of potential endocrine disruptors for (anti)androgenic and (anti)estrogenic properties. Copyright 1999 Academic Press. Toxicology and Applied Pharmacology, v 155, n 2, March 1, 1999, p150-160 (ID taap.1998.8598) A Compartmental Model for the Kinetics of Mercury Vapor in Humans Fredrik Jonsson, Gunilla Sandborgh-Englund, Gunnar Johanson Toxicology and Applied Pharmacology, v 155, n 2, March 1, 1999, p161-168 (ID taap.1998.8585) Synergistic Protective Effects of Selected Arginine Analogues against Sulphur Mustard Toxicity in Neuron Culture Thomas W. Sawyer Previous studies in this laboratory have shown that the arginine analogues l-thiocitrulline (l-TC) and l-nitroarginine methyl ester (l-NAME) have potent protective activity against sulphur mustard (HD) toxicity that was not related to their nitric oxide synthase inhibiting activities. Furthermore, their characteristics of action suggested that they act at different sites to exert their protection. l-TC acted rapidly (minutes of preincubation) and was equipotent in protecting either immature or mature cultures of chick embryo neurons against the toxicity of HD while l-NAME was only effective in mature cultures. Maximal protection occurred at mM drug concentrations and increased the LC50 of HD by 200 % (l-NAME) to 800 % (l-TC). l-NAME did not alter the efficacy of l-TC in immature cultures but increased the LC50 up to 1500 % in mature cultures. Removal of l-NAME eliminated this synergism, leaving only the persistent protection of l-TC. l-Nitroarginine and d-NAME also increased the protective efficacy of l-TC in a concentration-related manner in mature cultures. The timing of drug administration before or after HD culture exposure was critical. Drug coadministration resulted in synergistic protection only when l-TC was added to the cultures prior to HD treatment. Thus, synergistic protective effects were also achieved when l-NAME was added up to 8 h after HD exposure, if they were pretreated with l-TC. Based on these findings, it is proposed that HD initiates its toxicity extremely rapidly through a cell surface-mediated event that can be blocked by l-TC. A signal is transduced into the cell that results in an additional event or lesion that manifests itself several hours downstream. This event/lesion progresses to cell death unless blocked reversibly by l-NAME. Copyright 1999 Academic Press. Toxicology and Applied Pharmacology, v 155, n 2, March 1, 1999, p169-176 (ID taap.1998.8588) Ah Receptor and ARNT Protein and mRNA Concentrations in Rat Prostate: Effects of Stage of Development and 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Treatment Rebecca J. Sommer, Katherine Marks Sojka, Richard S. Pollenz, Paul S. Cooke, Richard E. Peterson Effects of stage of development and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure on aryl hydrocarbon receptor (AhR) and AhR nuclear translocator (ARNT) protein concentrations in reproductive organs of male rats were determined. AhR protein levels in developing rat ventral and dorsolateral prostate decreased with age, declining approximately 70 % between Postnatal Days (PND) 1 and 21. ARNT protein levels also decreased with age in dorsolateral, but not ventral prostate. The developmental decreases in prostatic AhR and ARNT protein were associated with decreases in AhR and ARNT mRNA. AhR and ARNT protein concentrations in fetal urogenital sinus on Gestation Days (GD) 16, 18, and 20 were similar to levels in ventral prostate on PND 7. TCDD exposure of adult male rats (0.2, 1, 5, or 25 µg/kg po, 24 h) decreased AhR but not ARNT protein in ventral and dorsolateral prostate, vas deferens, and epididymis. In utero and lactational TCDD exposure (1.0 µg/kg dam po, GD 15) did not alter ARNT levels but reduced prostatic AhR protein levels on PND 7 and delayed the developmental decrease in AhR protein in ventral and dorsolateral prostate. Finally, pretreatment of rat pups for 24 h with TCDD (5 µg/kg ip) down-regulated prostatic AhR protein on PND 7, but not on PND 1. Thus, prostatic AhR and ARNT protein and mRNA levels are regulated with age, whereas only AhR protein concentration is altered by TCDD exposure. Because in utero and lactational TCDD exposure only decreased prostatic AhR on PND 7, it is unlikely that down-regulation of AhR is the mechanism by which perinatal TCDD exposure impairs prostate development.Copyright 1999 Academic Press. Toxicology and Applied Pharmacology, v 155, n 2, March 1, 1999, p 177-189 (ID taap.1998.8597) Methimazole Toxicity in Rodents: Covalent Binding in the Olfactory Mucosa and Detection of Glial Fibrillary Acidic Protein in the Olfactory Bulb Ulrika Bergman, Eva B. Brittebo Toxicology and Applied Pharmacology, v 155, n 2, March 1, 1999, p190-200 (ID taap.1998.8590) Physiologically Based Modeling of 1,2,4-Trimethylbenzene Inhalation Toxicokinetics J. Jarnberg, G. Johanson Toxicology and Applied Pharmacology, v 155, n 3, March 15, 1999, p203-214 (ID taap.1998.8596) ATP-Dependent Colchicine Transport by Human Erythrocyte Glutathione Conjugate Transporter Sanjay Awasthi, Sharad S. Singhal, Utpal Pandya, Sanjiv Gopal, Piotr Zimniak, Shivendra V. Singh, Yogesh C. Awasthi Toxicology and Applied Pharmacology, v 155, n 3, March 15, 1999, p215-226 (ID taap.1998.8617) Atypical Antipsychotic-Induced Neutropenia in Dogs Meike Lorenz, Winston E. Evering, Anne Provencher, Julia T. Blue, Hugh B. Lewis, Jeff R. Hazelette, Parthasarathi Rajagopalan, Paul C. Meunier, Bruce D. Car Toxicology and Applied Pharmacology, v 155, n 3, March 15, 1999, p227-236 (ID taap.1998.8582) Developmental Vasculotoxicity Associated with Inhibition of Semicarbazide-Sensitive Amine Oxidase S. D. Langford, M. B. Trent, A. Balakumaran, P. J. Boor Toxicology and Applied Pharmacology, v 155, n 3, March 15, 1999, p237-244 (ID taap.1998.8602) Cytotoxicity and Induction of Proinflammatory Cytokines from Human Monocytes Exposed to Fine (PM2.5) and Coarse Particles (PM10-2.5) in Outdoor and Indoor Air Christian Monn, Susanne Becker Toxicology and Applied Pharmacology, v 155, n 3, March 15, 1999, p245-252 (ID taap.1998.8591) Perinatal Exposure to Aged and Diluted Sidestream Cigarette Smoke Produces Airway Hyperresponsiveness in Older Rats Jesse P. Joad, John M. Bric, Janice L. Peake, Kent E. Pinkerton Toxicology and Applied Pharmacology, v 155, n 3, March 15, 1999, p253-260 (ID taap.1998.8612) Stimulation of Oscillatory Uterine Contraction by the PCB Mixture Aroclor 1242 May Involve Increased [Ca2+]i through Voltage-Operated Calcium Channels Jeehyeon Bae, Edward L. Stuenkel, Rita Loch-Caruso Toxicology and Applied Pharmacology, v 155, n 3, March 15, 1999, p261-272 (ID taap.1998.8614) Acetaminophen-Induced Proliferation of Breast Cancer Cells Involves Estrogen Receptors Eugenia Harnagea-Theophilus, Samantha L. Gadd, April H. Knight-Trent, George L. DeGeorge, Michael R. Miller Previous studies have shown that acetaminophen, a common analgesic/antipyretic, induces proliferation of cultured breast cancer cells containing both estrogen and progesterone receptors (ER+/PR+). The main objective of this study was to evaluate the involvement of ERs in this effect. First, the effects of therapeutic acetaminophen concentrations were compared in breast cancer cells with high ERs and in T47Dco cells with lower ERs, to determine if acetaminophen-induced proliferation depends on ER levels. Second, the effects of two antiestrogens (ICI 182,780 and 4'-hydroxytamoxifen) on acetaminophen-induced proliferation were determined in three human breast cancer cell lines: two ER+/PR+ (MCF7, T47D) and one ER-/PR- (MDA-MB-231). Third, ER binding assays were performed in MCF7 cells to determine if acetaminophen competed with estradiol for binding to ERs. Proliferation endpoints monitored included percent cells in the DNA synthesis phase of the cell cycle, 3H-thymidine incorporation into DNA, and cell number. Acetaminophen did not induce DNA synthesis in T47Dco cells, but did in cells with higher ER levels, suggesting high ER levels are necessary for acetaminophen to induce proliferation. Antiestrogens inhibited acetaminophen-induced proliferation in ER+/PR+ cells while no effects were observed in ER-/PR- cells, further supporting ER involvement. However, acetaminophen did not compete with estradiol for binding to ERs in ER+/PR+ cells. Collectively, these data suggest that acetaminophen induces breast cancer cell proliferation via ERs without binding to ERs like estradiol. The second purpose of this study was to determine if acetaminophen is estrogenic/antiestrogenic in vivo (uterotrophic assays). Acetaminophen has no antiestrogenic/estrogenic activity in mice or rats uteri. Copyright 1999 Academic Press. Toxicology and Applied Pharmacology, v 155, n 3, March 15, 1999, p273-279 (ID taap.1998.8619) Lead Activates Nuclear Transcription Factor kappaB, Activator Protein-1, and Amino-Terminal c-Jun Kinase in Pheochromocytoma Cells Govindarajan T. Ramesh, Sunil K. Manna, Bharat B. Aggarwal, Arun L. Jadhav Lead (Pb) is a ubiquitous environmental contaminant that produces variety of effects on the central and peripheral nervous system, induces inflammatory response, and modulates immune functions. Though increase in lipid peroxidation and reactive oxygen intermediates (ROI) have been observed in Pb-induced toxicity, the molecular mechanism underlying these effects is largely unknown. Since nuclear factor kappa B (NF-kappaB) and activator protein (AP-1) are known to be activated by oxidative stress, we hypothesized that Pb-induced effects may be modulated via these transcription factors. The effects of Pb on NF-kappaB, AP-1, and related kinases were studied in pheochromocytoma cells (PC-12). Our results showed that treatment of murine PC-12 cells with Pb resulted in activation of NF kappaB and degradation of IkappaBalpha (the inhibitory subunit of NF-kappaB). Pb-induced NF-kappaB dependent gene expression was also enhanced. The binding of Pb-induced NF-kappaB to DNA was blocked by antibodies for p65 and p50 but not by c-Rel or nonspecific antibodies such as cyclin D-1 and preimmune serum, suggesting that NF-kappaB consisted of p65 and p50 subunits. Similar to its effects on NF-kappaB, Pb also activated AP-1 in a time- and dose-dependent manner. Besides activating these transcription factors, Pb was also found to upregulate the related kinases such as mitogen activated protein kinase kinase (MEK) and c-Jun N-terminal kinase (JNK) (also known as stress-activated protein kinase) in a dose- and time-dependent manner. Thus, these results suggest that NF-kappaB, AP-1, MEK, and JNK may be important mediators of Pb-induced signaling in gene expression mediating inflammatory response and immunomodulation. Copyright 1999 Academic Press. Toxicology and Applied Pharmacology, v 155, n 3, March 15, 1999, p280-286 (ID taap.1999.8624) The Nature of Halogen Substitution Determines the Mode of Cytotoxicity of Halopropanols Alison H. Hammond, Michael J. Garle, Jeffrey R. Fry Toxicology and Applied Pharmacology, v 155, n 3, March 15, 1999, p287-291 (ID taap.1998.8610) Материал подготовил |