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6. Toxicity

Author

Radatz, Matthias, Nau, Heinz, Parnham, Michael J., editor, Bruinvels, J., editor, and Löscher, Wolfgang, editor

Published
1999
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15. Determination of colchicine residues in sheep serum and milk using high-performance liquid chromatography combined with electrospray ionization ion trap tandem mass spectrometry

Author

Hamscher, Gerd, Priess, Beate, Nau, Heinz, and Panariti, Edmond

Subjects
Colchicine -- Research, Chemistry, Analytic -- Research, Ionization -- Research, Liquid chromatography -- Research, Chemistry
Abstract

Colchicine is a naturally occurring alkaloid used in human and veterinary medicine. It shows genotoxicity in in vitro and in vivo systems even at low concentrations. Therefore, no ADI has been established, and colchicine has been included in Annex IV of Council Regulation (EEC) No. 2377/90. No abuse of this drug in intensive livestock farming has yet been reported. However, there may be a natural route of entry for this compound into the food chain when Colchicum autumnale is consumed by animals kept outdoors. To address this concern, we developed and validated a highly sensitive and selective quantitative LC-ESI-MS-MS method for the detection of colchicine in sheep serum and milk. For sample pretreatment, all samples were liquid--liquid extracted with phosphate buffer (pH 8.0) and dichloromethane. LC separation was carried out on an RP C18 column employing a 0.5% formic acid/acetonitrile gradient system. The recoveries in both matrixes at a concentration range from 0.0005 to 1 mg/L were >80% with RSDs of

Published
2005

17. Antagonism of hypervitaminosis a-induced anterior neural tube closure defects with a methyl-donor deficiency in murine whole-embryo culture

Author

Santos-Guzman, Jesus, Arnhold, Thomas, Nau, Heinz, Wagner, Conrad, Fahr, Sharon H., Mao, Gloria E., Caudill, Marie A., Wang, Jennie C., Henning, Susanne M., Swendseid, Marian E., and Collins, Michael, American writer

Subjects
Hypervitaminosis -- Complications, Birth defects -- Causes of, Food/cooking/nutrition
Abstract

The interaction of a dietary excess of vitamin A (retinoid) and deficiency of methyl-donor compounds was examined in murine early-organogenesis embryonic development. Female mice were fed one of six diets from the time of vaginal plug detection until gestational d 8.0, when embryos were removed and grown in whole embryo culture for 46 h, using serum from rats fed the same diet for 36 d as the culture medium. The six diets were either methyl-donor deficient (designated -FCM: devoid of folic acid, choline and supplemental L-methionine, but having methionine as a component of the protein portion of the diet) or methyl-donor sufficient (designated +FCM: containing folic acid, choline and L-methionine supplementation), in combination with one of three concentrations of retinyl palmitate (0.016, 0.416 or 4.016 g/kg diet). The high dose of retinyl palmitate induced a failure of anterior neuropore closure and hypoplasia of the visceral arches, both of which were significantly ameliorated by simultaneous administration of the methyl-donor-deficient diet. The primary acidic retinoid detected in the rat serum was 9,13-di-cis-retinoic acid, although we hypothesize that teratogenic retinoids were formed by embryonic biotransformation of the retinyl esters to toxic metabolites. Biochemical measurements of metabolites in relevant pathways were performed. We propose that the amelioration of these malformations may be used to determine biochemical pathways critical for retinoid teratogenesis. KEY WORDS: * vitamin A * retinoid * methylation * neural tube * teratogenesis

Published
2003

25. Determination of persistent tetracycline residues in soil fertilized with liquid manure by high-performance liquid chromatography with electrospray ionization tandem mass spectrometry

Author

Hamscher, Gerd, Sczesny, Silke, Hoper, Heinrich, and Nau, Heinz

Subjects
Chemistry, Analytic -- Research, Mass spectrometry -- Usage, Liquid chromatography -- Usage, Tetracyclines -- Research, Manures -- Analysis, Chemistry
Abstract

Little is known about the occurrence and the fate of veterinary drugs in the environment. Therefore, a liquid chromatography/tandem mass spectrometry method was developed and employed to investigate in detail the distribution and persistence of the frequently used tetracyclines and tylosin in a field fertilized with liquid manure on April 2000 and April 2001; soil sampling was performed in May 2000, November 2000, and May 2001. We detected 4.0 mg/kg tetracycline and 0.1 mg/kg chlortetracycline in the liquid manure of April 2000, as well as comparable amounts in the liquid manure of April 2001. In the soil samples of May 2001, the highest average concentrations of 86.2 (0-10 cm), 198.7 (10-20 cm), and 171.7 [micro]g/kg (20-30 cm) tetracycline and 4.6-7.3 [micro]g/kg chlortetracycline (all three sublayers) were found. At soil depths between 30 and 90 cm, as well as in soil or groundwater, tetracyclines could not be detected. In addition, oxytetracycline and tylosin could not be detected in any sample investigated. We conclude that tetracyclines enter the environment in significant concentrations via repeated fertilizations with liquid manure, build up persistent residues, and accumulate in soil. Therefore, tetracyclines may have a potential risk and investigations on the environmental effects of these antibiotics are necessary.

Published
2002

26. Porcine intestinal metabolism of excess vitamin A differs following vitamin A supplementation and liver consumption. (Nutrient Metabolism)

Author

Arnhold, Thomas, Nau, Heinz, Meyer, Silke, Rothkoetter, Hermann J., and Lampen, Alfonso D.

Subjects
Vitamin A in animal nutrition -- Physiological aspects, Diet -- Physiological aspects, Teratogenesis -- Risk factors, Dietary supplements -- Adverse and side effects, Food/cooking/nutrition
Abstract

Vitamin A is a well-established teratogen in all animal species. A number of case reports also suggest a teratogenic potential of vitamin A in humans. A possible teratogenic risk of dietary liver vitamin A intake, the kinetics of vitamin A and its metabolites in humans after intake of either a vitamin A supplement or a liver meal have been studied. Major differences were described for the kinetics of all-trans-retinoic acid (all-trans-RA), which occurred at much higher concentrations after supplementation than after liver consumption. Therefore, we investigated whether the intestine may be responsible for the differences in vitamin A metabolism after supplementation or liver feeding. We found that cytosolic fractions of porcine enterocytes oxidized retinol to all-trans-RA in vitro with a [K.sub.m] of 94-96/[micro] mol/L and a [V.sub.max] of 7.9-8.6 pmol/(min * mg protein). In an in vivo approach, the portal vein and the central vein (external jugular vein) of a pig were cannulated. In two subsequent experiments, the pig was given a vitamin A supplement or liver. Plasma samples were taken from portal and central veins. Comparison of retinoid levels in these veins indicated that all-trans-RA was already formed from supplemental vitamin A in the intestine and released into the systemic circulation. Two major metabolic pathways were additionally present in the pig, leading to the formation of glucuronides of all-trans-RA and retinol itself. Our results indicate that intestinal metabolism contributes to the elevated levels of all-trans-RA in the systemic circulation after supplementation with vitamin A, but not after consumption of liver. J. Nutr. 132: 197-203, 2002. KEY WORDS: * retinol * retinoic acid * vitamin A * liver * supplementation * intestine * metabolism

Published
2002

33. CONTRIBUTORS

Author

Abbasi, Soraya, primary, Abman, Steven H., additional, Adamson, S. Lee, additional, Adzick, N. Scott, additional, Albertine, Kurt H., additional, Alman, Benjamin A., additional, Altschuler, Steven M., additional, Anderson, Page A.W., additional, Anthony, Russell V., additional, Aron, Elisabeth A., additional, Aslan, Ahmet R., additional, Asselin, Jeanette M., additional, Auten, Richard L., additional, Avery, Mary Ellen, additional, Avner, Ellis D., additional, Baldwin, H. Scott, additional, Ballard, Philip L., additional, Bancalari, Eduardo, additional, Barker, David J.P., additional, Barker, Pierre M., additional, Battaglia, Frederick C., additional, Beauchamp, Gary K., additional, Beesley, Jacqueline, additional, Benchimol, Corinne, additional, Bennet, Laura, additional, Berg, Robert A., additional, Berry, Gerard T., additional, Berseth, Carol Lynn, additional, Bhutani, Vinod K., additional, Blecher, Stan R., additional, Blood, Arlin B., additional, Bolender, David L., additional, Boyd, Robert D.H., additional, Brace, Robert A., additional, Brewer, Eileen D., additional, Brophy, Patrick D., additional, Broussard, Delma L., additional, Bucuvalas, John C., additional, Burrin, Douglas G., additional, Byrne, Bridgette M.P., additional, Byskov, Anne Grete, additional, Cairo, Mitchell S., additional, Cannon, Barbara, additional, Caplan, Michael S., additional, Caplin, Neil, additional, Carlson, Susan E., additional, Carlton, David P., additional, Cashore, William J., additional, Chaiworapongsa, Tinnakorn, additional, Chemtob, Sylvain, additional, Chevalier, Robert L., additional, Chheda, Sadhana, additional, Christensen, Robert D., additional, Chu, David H., additional, Clancy, Robert Ryan, additional, Clandinin, M. Thomas, additional, Clark, David A., additional, Cleary-Goldman, Jane, additional, Clyman, Ronald I., additional, Cohen, Pinchas, additional, Corey, Howard E., additional, Cotton, Robert B., additional, Cowart, Beverly J., additional, Cowett, Richard M., additional, Crombleholme, Timothy M., additional, Crowe, James E., additional, Cuttler, Leona, additional, D'Alton, Mary E., additional, Danzer, Enrico, additional, De León, Diva D., additional, Delivoria-Papadopoulos, Maria, additional, Diaz, George A., additional, Dickinson, Chris J., additional, Dormans, John P., additional, Durand, David J., additional, Edwards, A. David, additional, Ennever, John F., additional, Erickson, Robert P., additional, Erol, Bulent, additional, Fahim, Mohamed A., additional, Feld, Leonard G., additional, Feldman, Miguel, additional, Fernandez, Lucas G., additional, Field, Douglas G., additional, Fisher, Delbert A., additional, Fox, William W., additional, Frank, Hans-Georg, additional, Friedlich, Philippe S., additional, Friedman, Aaron L., additional, Friedman, Joshua R., additional, Garland, Marianne, additional, Gervasi, Maria-Teresa, additional, Gibson, James B., additional, Gluckman, P.D., additional, Goldberg, Michael J., additional, Goldman, Armond S., additional, Goldstein, Gary W., additional, Gomez, R. Ariel, additional, Gondos, Bernard, additional, Grant, Denis M., additional, Green, Lucy R., additional, Greenspan, Jay S., additional, Grimberg, Adda, additional, Grindley, Justin C., additional, Gross, Ian, additional, Guignard, Jean-Pierre, additional, Gunn, Alistair J., additional, Haddad, Gabriel G., additional, Hagstrom, J. Nathan, additional, Halpern, Kathrin V., additional, Hambidge, K. Michael, additional, Hamosh, Margit, additional, Hanson, Mark A., additional, Haramati, Aviad, additional, Harding, Richard, additional, Harris, Mary Catherine, additional, Haxhiu, Musa A., additional, Hay, William W., additional, Hayward, Anthony R., additional, Heird, William C., additional, Herrera, Emilio, additional, Hill, Harry R., additional, Hillemeier, A. Craig, additional, Hirschhorn, Kurt, additional, Hoath, Steven B., additional, Horst, David A., additional, Hunley, Tracy E., additional, Hunter, Christian J., additional, Husain, Shahid M., additional, Hutson, Susan M., additional, Ikegami, Machiko, additional, Inder, Terrie E., additional, Jobe, Alan H., additional, Johnson, Lois H., additional, Johnston, Michael V., additional, Johnston, Richard B., additional, Jones, Deborah P., additional, Jones, Peter Lloyd, additional, Jose, Pedro A., additional, Kalhan, Satish C., additional, Kallapur, Suhas, additional, Kaplan, Stanley, additional, Karpen, Saul J., additional, Kashyap, Sudha, additional, Kaskel, Frederick J., additional, Levitt Katz, Lorraine E., additional, Kaufmann, Peter, additional, Keeney, Susan E., additional, Kilpatrick, Laurie, additional, Kinsella, John P., additional, Kirby, Margaret L., additional, Kleinman, Charles S., additional, Kogan, Barry A., additional, Koldovský, Otakar, additional, Kon, Valentina, additional, Kopecky, Ernest A., additional, Korchak, Helen M., additional, Koren, Gideon, additional, Krebs, Nancy F., additional, Kulik, Thomas J., additional, Kutikov, Jessica Katz, additional, La Pine, Timothy R., additional, Lasunción, Miguel Angel, additional, Laterra, John, additional, Lee, P.C., additional, Levine, Fred, additional, Lewis, David B., additional, Liacouras, Chris A., additional, Linshaw, Michael A., additional, Lister, George, additional, Loomis, Cynthia A., additional, Lorenz, John M., additional, Lobritto, Steven, additional, Lugo, Ralph A., additional, Maheshwari, Akhil, additional, Manco-Johnson, Marilyn J., additional, Mantilla, Carlos B., additional, Mariscalco, M. Michele, additional, Maródi, László, additional, Maršál, Karel, additional, Martin, Richard J., additional, Matthews, Dwight E., additional, McDuffie, Marcia, additional, McGowan, Jane E., additional, McManaman, James, additional, Mehmet, Huseyin, additional, Mennella, Julie A., additional, Metinko, Andrew, additional, Miller, Martha J., additional, Monagle, Paul, additional, Mortola, Jacopo P., additional, Mott, Glen E., additional, Mughal, M. Zulficar, additional, Mulroney, Susan E., additional, Munshi, Upender K., additional, Myatt, Leslie, additional, Myers, Margaret A., additional, Namgung, Ran, additional, Narkewicz, Michael R., additional, Nau, Heinz, additional, Nedergaard, Jan, additional, Neville, Margaret C., additional, Nielsen, Heber C., additional, Nogee, Lawrence M., additional, Noori, Shahab, additional, Norwitz, Errol R., additional, Norwood, Victoria F., additional, Ogata, Edward S., additional, Ohls, Robin K., additional, Olson, Thomas A., additional, Omari, Taher I., additional, Padbury, James F., additional, Palmert, Mark R., additional, Parravicini, Elvira, additional, Pereira, Gilberto R., additional, Perlman, Jeff M., additional, Philipps, Anthony F., additional, Pickoff, Arthur S., additional, Pinal, C.S., additional, Pleasure, David, additional, Pleasure, Jeanette, additional, Plonait, Sabine Luise, additional, Polin, Richard A., additional, Polk, Daniel H., additional, Pomeroy, Scott L., additional, Possmayer, Fred, additional, Post, Martin, additional, Power, Gordon G., additional, Prada, Jorge A., additional, Putet, Guy, additional, Pysher, Theodore J., additional, Quinn, Graham E., additional, Rabinovitch, Marlene, additional, Randell, Scott H., additional, Regnault, Timothy R.H., additional, Rieder, Michael J., additional, Rigatto, Henrique, additional, Rintoul, Natalie E., additional, Robillard, Jean E., additional, Robinson, Julian, additional, Romero, Roberto, additional, Rooney, Seamus A., additional, Rose, James C., additional, Rosenfeld, Charles R., additional, Ross, Arthur J., additional, Rudolph, Colin D., additional, Sahni, Rakesh, additional, Sarnat, Harvey B., additional, Satlin, Lisa M., additional, Saugstad, Ola Didrik, additional, Schibler, Kurt R., additional, Schulze, Karl, additional, Schwartz, Jeffrey, additional, Sedin, Gunnar, additional, Segar, Jeffrey L., additional, Seri, Istvan, additional, Setchell, Kenneth, additional, Shaffer, Thomas H., additional, Shaul, Philip W., additional, Shenai, Jayant P., additional, Sibley, Colin P., additional, Sieck, Gary C., additional, Siler-Khodr, Theresa M., additional, Silverstein, Faye S., additional, Simmons, Rebecca A., additional, Sivieri, Emidio M., additional, Slavkin, Harold C., additional, Snyder, Evan Y., additional, Snyder, Jeanne M., additional, Solhaug, Michael J., additional, Southern, Kevin W., additional, Spitzer, Adrian, additional, Spitzer, Alan R., additional, Stanley, Charles A., additional, Stapleton, F. Bruder, additional, Styne, Dennis, additional, Sweeney, William E., additional, Talner, Norman S., additional, Thornton, Paul S., additional, Truog, William Edward, additional, Tsang, Reginald C., additional, Tufro, Alda, additional, Ullrich, Nicole J., additional, Un, Socheata, additional, Van Aerde, John E., additional, van de Ven, Carmella, additional, van Goudoever, Johannes B., additional, Vannucci, Robert C., additional, Vannucci, Susan J., additional, van Tuyl, Minke, additional, Volpe, Joseph J., additional, Wallin, Reidar, additional, Warburton, David, additional, Ward, Robert M., additional, Weitkamp, Joern-Hendrik, additional, Werlin, Steven L., additional, Werner, Lynne A., additional, Wert, Susan E., additional, Westergaard, Lars Grabow, additional, Whitsett, Jeffrey A., additional, Wilke, Michaelann, additional, Williams, John V., additional, Williamson, Dermot H., additional, Winkelstein, Jerry A., additional, Winter, Jeremy S.D., additional, Woelkers, Douglas A., additional, Wolfson, Marla R., additional, Woroniecki, Robert P., additional, Yassir, Walid K., additional, Yip, Stephen, additional, Yoder, Mervin C., additional, Young, Sharla, additional, Young, Stephen L., additional, and Zhou, Dan, additional

Published
2004
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41. Embryotoxic doses of vitamin A to rabbits result in low plasma but high embryonic concentrations of all-trans-retinoic acid: risk of vitamin A exposure in humans

Author

Tzimas, Georg, Collins, Michael, American writer, Burgin, Heinrich, Hummler, Hans, and Nau, Heinz

Subjects
Vitamin A -- Health aspects, Rabbits -- Food and nutrition, Tretinoin -- Physiological aspects, Human embryo -- Physiological aspects, Food/cooking/nutrition
Abstract

Retinoid pharmacokinetics were examined in plasma, placenta and embryos of gestational d 12 rabbits following application of an embryotoxic dosing regimen (10 mg retinyl palmitate/kg body wt per day from gestational d 7 to 12). Vehicle-treated or untreated rabbits served as controls. Physiological concentrations of all-trans-retinoic acid (all-trans-RA) and 13-cis-RA in rabbit plasma (5-8.33 nmol/L) were very close to the endogenous levels in human plasma. In addition, we identified endogenous all-trans-RA, 3,4-didehydroretinol and 3,4-didehydroretinoic acid in rabbit embryo. Following the last retinyl palmitate administration, apparent steady-state concentrations of all retinoids were reached in the examined compartments of rabbits. The major polar retinoid in plasma was 9,13-di-cis-RA, but its embryonic concentrations were only about 6% of those in plasma. In the embryo, retinol and its esters were found at high concentrations; lower amounts of all-trans-4-oxo-RA and the newly identified 14-hydroxy-4,14-retro-retinol could also be measured. Embryonic concentrations of all-trans-RA were about 100% higher than endogenous levels. The overall exposure of the embryo to this retinoid was, however, substantial. Embryonic area under the concentration time curve values strongly suggest that the embryotoxicity of the applied dosing regimen is mainly due to the action of all-trans-RA. A very remarkable finding of this study is the marginal increase of plasma concentrations of all-trans-RA over their endogenous levels, which is comparable to the human situation after vitamin A intake. This analogy indicates that high vitamin A intake may be associated with a higher risk for teratogenic effects in humans even in the absence of high elevation of plasma all-trans-RA levels. J. Nutr. 126: 2159-2171, 1996. INDEXING KEY WORDS: * embryotoxicity * rabbits * retinoic acid * retinol * vitamin A

Published
1996

42. Methionine reduces the valproic acid-induced spina bifida rate in mice without altering valproic acid kinetics

Author

Ehlers, Katharine, Elmazar, Mohamed M.A., and Nau, Heinz

Subjects
Methionine -- Health aspects, Valproic acid -- Research, Spina bifida -- Health aspects, Mice -- Food and nutrition, Food/cooking/nutrition
Abstract

The antiepileptic drug valproic acid (VPA) is an established human teratogen causing spina bifida aperta. We recently developed a mouse model in which spina bifida aperta and occulta are induced with VPA. In a search for protection against neural tube defects, we investigated the effect of methionine on the incidence of VPA-induced spina bifida in the mouse. To induce spina bifida, we injected VPA (350 mg VPA-Na/kg body weight) subcutaneously three times on d 9 of gestation at 0, 6 and 12 h. in some mice, L-methionine (3 X 70 mg/kg body weight) was injected intraperitoneally 30 min before each VPA administration. When fetuses were examined on d 18, methionine treatment slightly reduced the VPA-induced spina bifida aperta rate from 5 to 1% (P > 0.05, no significant difference). The incidence of VPA-induced spina bifida occulta (90%) was significantly lower (28%) when methionine was also administered (P < 0.05). Examination on d 10 showed that the number of embryos in the mice administered VPA and methionine having an open neuroporus posterior was significantly lower than in mice administered VPA alone (P < 0.05). Pharmacokinetic studies indicated that VPA concentrations in maternal plasma and embryo did not differ between the two groups. Methionine reduces VPA-induced spina bifida in mice without altering VPA kinetics. INDEXING KEY WORDS: spina bifida; valproic acid; methionine; pharmacokinetics; mice

Published
1996

50. Endogenous status of retinoids and their cytosolic binding proteins in limb buds of chick vs mouse embryos

Author

Scott, Willlam J., Jr., Walter, Rosemarie, Sass, Jorn Oliver, Collins, Michael, American writer, Nau, Heinz, and Trimas, Georg

Subjects
Retinoids -- Research, Carrier proteins -- Physiological aspects, Extremities (Anatomy) -- Growth, Biological sciences
Abstract

A study of the cytosolic binding proteins and retinoids in the limb buds of mice and aged chick embryos to determine the endogenous position of retinoids reveals that the chick limb bud has higher cytosolic and ligand binding protein levels than mice, indicating that the distribution of retinoids and proteins varies in the two embryos. The free retinoic acid (RA) concentration is higher in chick than in mice, and the former displays a putative retinoic acid gradient. RA and 3, 4-didehydroretinoic acid levels are less than cytosolic retinol binding protein levels in the chick limb bud.

Published
1994

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