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April 9 - 11
João Laranjinha, Leonor Almeida, Paulo Oliveira, Carlos Palmeira
Metabolic Toxicology: From Pathway to Organism”
Organized by the Cell and Molecular Toxicology Research Area
The course is the 2008 edition of the “International Courses on Toxicology”, organized by the Cell and Molecular Toxicology Group of the CNC on a yearly basis. The 2008 edition will be held at the Auditório da Reitoria of the University of Coimbra (free admission)

The objective of this course is to provide theoretical information on several aspects of metabolic toxicity. Metabolic alterations caused by disease conditions or xenobiotics will be presented by respected scientists in the field. One particular example will be drug-induced mitochondrial toxicity. Arguments will be provided for the necessary development of high throughput screening methods to evaluate mitochondrial toxicity of novel molecules designed by pharmaceutical companies. The course is open to all interested students, staff, researchers and faculty. One afternoon will be dedicated to the CNC doctoral student presentations (see below) and another one to research presentations by Ph.D. students or very recent Post-Docs with work performed in the field.

Invited speakers:
·         Vitor M. C. Madeira (Department of Biochemistry and CNC, University of Coimbra, Portugal)
·         Yvonne Will (Early Safety Differentiation Group, Pfizer Groton, CT, USA)
·         Elaine Holmes (Imperial College of London, UK)
·         Piero Portincasa (University Medical School of Bari, Italy)
·         Maria de Lourdes Bastos (Faculty of Pharmacy, University of Porto, Portugal)
·         Rui A. Carvalho (NMR Unit, Department of Biochemistry and CNC, University of Coimbra, Portugal)
·         Carlos M. Palmeira (IMAR and CNC, University of Coimbra, Portugal)
Selected references from the speakers:
Vitor M. C. Madeira
·         Moreno AJ, Serafim TL, Oliveira PJ, Madeira VM. Inhibition of mitochondrial bioenergetics by carbaryl is only evident for higher concentrations -- Relevance for carbaryl toxicity mechanisms. Chemosphere. 2007 Jan;66(3):404-11.
·         Monteiro JP, Jurado AS, Moreno AJ, Madeira VM. Toxicity of methoprene as assessed by the use of a model microorganism. Toxicol In Vitro. 2005 Oct;19(7):951-6.
·         Peixoto F, Vicente JA, Madeira VM. The herbicide dicamba (2-methoxy-3,6-dichlorobenzoic acid) interacts with mitochondrial bioenergetic functions.
·         Arch Toxicol. 2003 Jul;77(7):403-9.
Yvonne Will
·         Dykens JA, Will Y. The significance of mitochondrial toxicity testing in drug development. Drug Discov Today. 2007 Sep;12(17-18):777-85..
·         Dykens JA, Bernal A, Capaldi RA, Will Y. Mitochondrial impairment by PPAR agonists and statins identified via immunocaptured OXPHOS complex activities and respiration. Toxicol Appl Pharmacol. 2007 Sep 15;223(3):277-87.
·         Will Y, Hynes J, Ogurtsov VI, Papkovsky DB. Analysis of mitochondrial function using phosphorescent oxygen-sensitive probes. Nat Protoc. 2006;1(6):2563-72.

Elaine Holmes
·         Beckonert O, Keun HC, Ebbels TM, Bundy J, Holmes E, Lindon JC, Nicholson JK. Metabolic profiling, metabolomic and metabonomic procedures for NMR spectroscopy of urine, plasma, serum and tissue extracts. Nat Protoc. 2007;2(11):2692-703.
·         Coen M, Hong YS, Cloarec O, Rhode CM, Reily MD, Robertson DG, Holmes E, Lindon JC, Nicholson JK. Heteronuclear (1)H-(31)P Statistical Total Correlation NMR Spectroscopy of Intact Liver for Metabolic Biomarker Assignment: Application to Galactosamine-Induced Hepatotoxicity. Anal Chem. 2007 Dec 1;79(23):8956-8966.
·         Lindon JC, Holmes E, Nicholson JK. Metabonomics in pharmaceutical R&D. FEBS J. 2007 Mar;274(5):1140-51.
Piero Portincasa
·         Petrosillo G, Portincasa P, Grattagliano I, Casanova G, Matera M, Ruggiero FM, Ferri D, Paradies G. Mitochondrial dysfunction in rat with nonalcoholic fatty liver Involvement of complex I, reactive oxygen species and cardiolipin. Biochim Biophys Acta. 2007 Oct;1767(10):1260-7.
·         Portincasa P. Non-alcoholic steatohepatitis (NASH): approaching more tailored and effective therapies. J Gastrointestin Liver Dis. 2007 Jun;16(2):167-9.
·         Portincasa P, Moschetta A, Petruzzelli M, Palasciano G, Di Ciaula A, Pezzolla A. Gallstone disease: Symptoms and diagnosis of gallbladder stones. Best Pract Res Clin Gastroenterol. 2006;20(6):1017-29.
Maria de Lourdes Bastos
·         Costa VM, Silva R, Ferreira LM, Branco PS, Carvalho F, Bastos ML, Carvalho RA, Carvalho M, Remião F. Oxidation process of adrenaline in freshly isolated rat cardiomyocytes: formation of adrenochrome, quinoproteins, and GSH adduct. Chem Res Toxicol. 2007 Aug;20(8):1183-91.
·         Capela JP, Macedo C, Branco PS, Ferreira LM, Lobo AM, Fernandes E, Remião F, Bastos ML, Dirnagl U, Meisel A, Carvalho F. Neurotoxicity mechanisms of thioether ecstasy metabolites. Neuroscience. 2007 Jun 8;146(4):1743-57.
·         19: Related Articles, LinksCapela JP, Meisel A, Abreu AR, Branco PS, Ferreira LM, Lobo AM, Remião F, Bastos ML, Carvalho F.Neurotoxicity of Ecstasy metabolites in rat cortical neurons, and influence of hyperthermia. J Pharmacol Exp Ther. 2006 Jan;316(1):53-61.

Rui A. Carvalho
·         Alves TC, Nunes PM, Palmeira CM, Jones JG, Carvalho RA. Estimating gluconeogenesis by NMR isotopomer distribution analysis of [(13)C]bicarbonate and [1-(13)C]lactate. NMR Biomed. (in press).
·         Duarte JM, Cunha RA, Carvalho RA. Different metabolism of glutamatergic and GABAergic compartments in superfused hippocampal slices characterized by nuclear magnetic resonance spectroscopy. Neuroscience. 2007 Feb 23;144(4):1305-13.
·         Carvalho RA, Rodrigues TB, Zhao P, Jeffrey FM, Malloy CR, Sherry AD. A (13)C isotopomer kinetic analysis of cardiac metabolism: influence of altered cytosolic redox and [Ca(2+)](o). Am J Physiol Heart Circ Physiol. 2004 Aug;287(2):H889-95.

Carlos M. Palmeira
·         Palmeira CM, Rolo AP, Berthiaume J, Bjork JA, Wallace KB. Hyperglycemia decreases mitochondrial function: The regulatory role of mitochondrial biogenesis. Toxicol Appl Pharmacol. 2007 Dec 1;225(2):214-20.
·         Rolo AP, Palmeira CM. Diabetes and mitochondrial function: role of hyperglycemia and oxidative stress. Toxicol Appl Pharmacol. 2006 Apr 15;212(2):167-78.
·         Rolo AP, Palmeira CM, Holy JM, Wallace KB. Role of mitochondrial dysfunction in combined bile acid-induced cytotoxicity: the switch between apoptosis and necrosis. Toxicol Sci. 2004 May;79(1):196-204.
Course schedule:
Day I – Wednesday, April 9
10:00-11:00 – Opening lecture: Vitor M. C. Madeira Oxygen Crafts
11:00-12:00 – Yvonne Will - Drug induced mitochondrial toxicity - overall review covering drug classes and organ toxicities
12:00-12:15 - Coffee break
12:15-13:15 – Piero Portincasa – Liver steatosis: the top of the metabolic iceberg
14:30 – 15:30 –Maria de Lourdes Bastos - Metabolic Bioactivation of Xenobiotics
15:30-17:00 – Afternoon presentations I (includes five short presentations from Portuguese Ph.D. students followed by general discussion). Moderators: Yvonne Will, Maria de Lourdes Bastos

Day II – Thursday, April 10
9:00-10:00 – Elaine Holmes – The role of metabolic profiling in toxicology
10:00-11:00 – Piero Portincasa – Cholesterol gallstone disease: a model of complexity
11:00-11:15 - Coffee break
11:15-12:15 – Yvonne Will - Techniques to identify drug-induced mitochondrial toxicity – positioning within the drug discovery process
14:30 – 15:30 – Rui A. Carvalho – Intermediary Metabolism in Mitochondria by 13C NMR Isotopomer Analysis
15:30-17:00 – Students presentations II (includes four presentations of Ph.D. students from the CNC doctoral programme). Moderators: Elaine Holmes, Piero Protincasa

Day III – Friday, April 11
9:00-10:00 – Elaine Holmes – Impact of the gut microbiome on toxicity and disease
10:00-11:00 – Maria de Lourdes Bastos - Parent compounds versus metabolites: comparative toxicity evaluation in different cellular models
11:15-12:15 - Coffee break
11:30-12:30 – Carlos M. Palmeira - Linking mitochondrial dysfunction to hyperglycemia: impact of mitochondrial fidelity and oxidative stress on diabetes and its complications
16:00 – 17:00 –Closing seminar: Yvonne Will - Drug development and safety- past, present and future
INFORMATIONS: Paulo J. Oliveira (pauloliv@ci.uc.pt)
Tasks for BEB students
The objective of your task is to present a fictitious grant proposal. Suppose that you want to obtain funding from a Government Agency and you are asked to provide a 15 minute (ONLY!) presentation of your proposal (Powerpoint-based). You have to give your best because you desperately need the money! You are also asked to divide the presentation in the following topics:
a) Background
b) Work hypothesis and aims
c) Detailed tasks (aims, methods and expected results)
d) Clinical relevance
You can also include items as budget requested, indicators (number of previewed publications resulting from the work), timetable or number of researchers involved.
There are a few rules involved on this:
a) The topic should fall within the subject of the course. Some ideas are:
a1) Investigating mitochondrial toxicity of molecules with clinical relevance (antineoplastics, statins, NRTIs, …)
a2) Design of safer formulations for hepatic drugs
a3) Investigation of cardiac (or other) toxicity induced by xenobiotics by NMR
a4) Decreasing diabetic complications by co-adjuvant therapies
a5) …
The originality and the contents of the proposals will be evaluated. Because of this, copies of or previously published works are not welcome and will hurt your final mark!
Students will be divided in the following manner:
1) Sofia Azevedo, Gil Cunha, João Santos
2) Ana Sofia Cabral, Susana Louros, Sueli Marques
3) Manuel Barroso, Lígia Silva, Nélio Gonçalves
4) Sara Figueiredo, Filipe Leal, Joana Marinho

Other Ph.D. students that wish to be evaluated in this course should speak with the organizer first (Paulo J. Oliveira, pauloliv@ci.uc.pt) in order to be divided by the existing groups. It is not necessary to present a written work. If necessary you can get in touch with me for further advice.
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