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Modelling a chemical signal in recombinant cells: Peroxlsome prollferation
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parallel to age but not to treatment-stage. The 15 ppmMVNG treated group of larval stage showed 80% tumor incidence at Smonth post treatment but the other age groups were only lO-15%. All 50 ppm-MNNG treated fish at lava1stage developed thyroid tumors at 5-month after treatment. In contrast, in this dose of MNNG-treated other life-stage groups showed significantly low incidences (1550%) than larval stage. These results demonstrated that the thyroid carcinogenicityof MNNG is age related in R. marmoratus. [lf Park E.-H. et al., Japan. J. Cancer Res.. 84.608 (19931. Key words: nk&smarmorahrs; age-dependency; thyroid tumor; MNNG
Modelllng a Chemlcsl Signal in Recombinant Calls: Peroxlsome Prollkmtlon K.Hoffrnann. R.E. Tjnes. Drvg Metabolikmi@opharmaceutics, Drug Safety Department Sandoz pharma Ltd., Base&Switzerland A recently identified protein of the steroid hormone receptor superfamily appears to be a primary participant in the signalling pathway leading to peroxisome proliferation 111.Peroxisome proliferation is a rare drug sideeffect. consisting with a disturbance in fatty acid homeostasis [2] and associated with non-genotoxic carcinogenesis. In order to model this mechanism under controlled circumstances the cDNA of the receptor was cloned from human and mouse tissue. The heterodimerization partner retinoid x receptor alpha (RxRa) [3] and the liver fatty acid binding protein (FABP) also have been cDNA cloned. lt appears that these three proteins participate in the signal transduction pathway leading to peroxisomal proliferation. By gone transfer these components were stably introduced into recombinant Chinese Hamster Ovary cells. These cells were also engineered to contain a chloramphenicol acetyl transferase “reporter gene” which can respond to chemical signals. Upon exposure of selected recombinant cell lines to sppropriate chemicals there appears to be authentic reconstitution of the signalling pathway. This technology should permit a rapid short-term testing protocol for “peroxisomal proliferation”: with uses for industrial, environmental chemical and pharmaceutical safety assessment. 111 Issemann. I. and Green, S.. Nature, 347,645 (1990). I21 GBttlicher,M.. Widmark. E.. Li. Q. and Gustafsson.J-A., Proc. Natl. Acad. Sci.. 89,4653 (1992). 131Kliewer. S. A.. Umesono. K.. Noonan. D. J.. Heyrnan, R. A. and Evans, R. A., Nature, 358.771 (1992). Key words: peroxisome proliferation; receptors; carcinogenesis; recombinant cells; in vitro
Disruption by Arachidonic Acid of Excitation Contraction Coupling in Electrically Stimulated Rat Cardiac Myocytes F?Hoffmann ’ . 0. Richards2. I. Heinroth-Hoffmann3, M. Toraason2. ’ Sterling Winthrop Pharmaceuticals Research Division, Dijon, Fiance; 2 National lnsritutefor Occupational Safety and Health, Cincinnati OH; 3 institute of Pharmacology and Toxic0fogKHale. Germany Recent reports suggest that arachidonic acid (AA) modulates cardiomyocyte function. In present experiments, effects AA on electricallyinducedfluctuationsof cytosolicfree Ca2+ concentration ([Ca2+]i) were investigated in neonatal rat ventricular myocytes using spectrofluorometricanalysis of fura-2-[Ca2+]i binding. Exposure to 25-100 PM AA produced a concentration dependent and reversiblediastolic and systolic increase in [Ca2+)i and eventually cessation of [Ca2+h transients within 7.4-14.5 min. Continued exposure to AA resulted in a Ca2+ overload and increased formation of lipid peroxidation products. Ca2+ overload was not prevented after depletion of sarcoplasmic reticulum Ca2+ pool by ryanodine pretreatment. Exposureof cardiomyocytes to AA (14 min) did not influence increase in [Ca7+h induced bv depolarizationwith 20 or 90 mM KCI but totally eliminated caffeine induced release of sarcoplasmic reticulum Ca2+. The data provide evidence that AA disrupts Ca2+ dynamics in cardiomyocytes by actions on sarcolemmal Ca2+ influx and sarcoplasmic reticulum Ca2+ handling possibly mediated via lipid peroxidation processes. Effects described here may contribute to cardiac damage under pathophysiological conditions, Key words: arachidonic acid; in vitro; cardiac myocytes; Ca2+ transients
Nonnaoplastic Pulmonary Lesions Occurred In Wistar Rats In Subchronlc T6xfcologlcal Studies Zs.Holl6, Zs. Korom. G. Boros. ToxicologicalResearch Centre Ltd. Veszprbm,Hungaty fntroduction and methods: Our observations are based on two 3-month and one one-year oral toxicity studies in WISTAR-rats. Careful clinical examinations were performed during the treatment periods.‘After the dosing periods macroscopic, light and electronmicroscopic investigationswere carried out in experimental animals.
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parallel to age but not to treatment-stage. The 15 ppmMVNG treated group of larval stage showed 80% tumor incidence at Smonth post treatment but the other age groups were only lO-15%. All 50 ppm-MNNG treated fish at lava1stage developed thyroid tumors at 5-month after treatment. In contrast, in this dose of MNNG-treated other life-stage groups showed significantly low incidences (1550%) than larval stage. These results demonstrated that the thyroid carcinogenicityof MNNG is age related in R. marmoratus. [lf Park E.-H. et al., Japan. J. Cancer Res.. 84.608 (19931. Key words: nk&smarmorahrs; age-dependency; thyroid tumor; MNNG
Modelllng a Chemlcsl Signal in Recombinant Calls: Peroxlsome Prollkmtlon K.Hoffrnann. R.E. Tjnes. Drvg Metabolikmi@opharmaceutics, Drug Safety Department Sandoz pharma Ltd., Base&Switzerland A recently identified protein of the steroid hormone receptor superfamily appears to be a primary participant in the signalling pathway leading to peroxisome proliferation 111.Peroxisome proliferation is a rare drug sideeffect. consisting with a disturbance in fatty acid homeostasis [2] and associated with non-genotoxic carcinogenesis. In order to model this mechanism under controlled circumstances the cDNA of the receptor was cloned from human and mouse tissue. The heterodimerization partner retinoid x receptor alpha (RxRa) [3] and the liver fatty acid binding protein (FABP) also have been cDNA cloned. lt appears that these three proteins participate in the signal transduction pathway leading to peroxisomal proliferation. By gone transfer these components were stably introduced into recombinant Chinese Hamster Ovary cells. These cells were also engineered to contain a chloramphenicol acetyl transferase “reporter gene” which can respond to chemical signals. Upon exposure of selected recombinant cell lines to sppropriate chemicals there appears to be authentic reconstitution of the signalling pathway. This technology should permit a rapid short-term testing protocol for “peroxisomal proliferation”: with uses for industrial, environmental chemical and pharmaceutical safety assessment. 111 Issemann. I. and Green, S.. Nature, 347,645 (1990). I21 GBttlicher,M.. Widmark. E.. Li. Q. and Gustafsson.J-A., Proc. Natl. Acad. Sci.. 89,4653 (1992). 131Kliewer. S. A.. Umesono. K.. Noonan. D. J.. Heyrnan, R. A. and Evans, R. A., Nature, 358.771 (1992). Key words: peroxisome proliferation; receptors; carcinogenesis; recombinant cells; in vitro
Disruption by Arachidonic Acid of Excitation Contraction Coupling in Electrically Stimulated Rat Cardiac Myocytes F?Hoffmann ’ . 0. Richards2. I. Heinroth-Hoffmann3, M. Toraason2. ’ Sterling Winthrop Pharmaceuticals Research Division, Dijon, Fiance; 2 National lnsritutefor Occupational Safety and Health, Cincinnati OH; 3 institute of Pharmacology and Toxic0fogKHale. Germany Recent reports suggest that arachidonic acid (AA) modulates cardiomyocyte function. In present experiments, effects AA on electricallyinducedfluctuationsof cytosolicfree Ca2+ concentration ([Ca2+]i) were investigated in neonatal rat ventricular myocytes using spectrofluorometricanalysis of fura-2-[Ca2+]i binding. Exposure to 25-100 PM AA produced a concentration dependent and reversiblediastolic and systolic increase in [Ca2+)i and eventually cessation of [Ca2+h transients within 7.4-14.5 min. Continued exposure to AA resulted in a Ca2+ overload and increased formation of lipid peroxidation products. Ca2+ overload was not prevented after depletion of sarcoplasmic reticulum Ca2+ pool by ryanodine pretreatment. Exposureof cardiomyocytes to AA (14 min) did not influence increase in [Ca7+h induced bv depolarizationwith 20 or 90 mM KCI but totally eliminated caffeine induced release of sarcoplasmic reticulum Ca2+. The data provide evidence that AA disrupts Ca2+ dynamics in cardiomyocytes by actions on sarcolemmal Ca2+ influx and sarcoplasmic reticulum Ca2+ handling possibly mediated via lipid peroxidation processes. Effects described here may contribute to cardiac damage under pathophysiological conditions, Key words: arachidonic acid; in vitro; cardiac myocytes; Ca2+ transients
Nonnaoplastic Pulmonary Lesions Occurred In Wistar Rats In Subchronlc T6xfcologlcal Studies Zs.Holl6, Zs. Korom. G. Boros. ToxicologicalResearch Centre Ltd. Veszprbm,Hungaty fntroduction and methods: Our observations are based on two 3-month and one one-year oral toxicity studies in WISTAR-rats. Careful clinical examinations were performed during the treatment periods.‘After the dosing periods macroscopic, light and electronmicroscopic investigationswere carried out in experimental animals.