MEMBERS

CAROLINA I GHANEM

Investigadora Adjunta CONICET. Jefe de Trabajos Prácticos Regular, Cátedra de Fisiopatología,FFYB. UBA

LIC. MARÍA BELÉN VIGO

Licenciada en Cs Biológicas. Universidad CAECE

RODRIGO LAGOS

Bioquímico. FFyB – UBA.

RESEARCH LINES

EFFECT OF ACETAMINOPHEN INTOXICATION ON THE MAIN ABCE TRANSPORTERS AND CENTRAL NERVOUS SYSTEM.

Acetaminophen (APAP) is a well-known analgesic and antipyretic. It is a safe drug within the therapeutic range, however APAP intoxication is the most common cause of acute liver failure (ALF) in north hemisphere. The final stages of the ALF are associated to hepatic encephalopathy, whose alterations at central nervous system (CNS) have been widely studied and are secondary to increased blood ammonia levels among other substances. However the possibility that the APAP produces CNS toxicity by itself and alterations in the permeability of the blood brain barrier (BBB) in the absence of IHA has been poorly studied. BBB permeability to different substances is determined for several factors as the presence of tight junctions in the endothelial cells, absence of fenestrations and the presence of substance transporters. Amond them, the ATP-dependent membrane transporters known as ABC (ATP-Binding Cassette) are very important in limiting drug acces to brain. These act as efflux pumps, eliminating endobiotics or drugs from the cell to the outside in ATP-dependent manner. Previously, we have shown that APAP induces the expression of ABC transporters in the liver and intestine. We also show that the administration of a toxic dose of APAP produces the nuclear translocation of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in the liver. This finding, added to the fact that the literature describes the role of the nuclear translocation of GAPDH in the pathophysiology of neurodegenerative diseases, suggest that the administration of APAP can produce the nuclear translocation of GAPDH in the CNS with consequences on the viability of the constitutive cells. Therefore, our aim is to study and characterize the effect produced by APAP administration on the CNS, mainly on the constituent cells of the glia and on the expression of the main transporters of the ABC family, which modify the penetrability of drugs in the BBB. Additionally, we are going to study  if the nuclear translocation of GAPDH at the CNS level could be the underlying molecular mechanism of the studied effects.

RECENT PUBLICATIONS

  1. ACETAMINOPHEN FROM LIVER TO BRAIN: NEW INSIGHTS INTO DRUG PHARMACOLOGICAL ACTION AND TOXICITY. Ghanem CI, Pérez MJ, Manautou JE, Mottino AD. Pharmacol Res. 2016 109:119-31. DOI: 10.1016/j.phrs.2016.02.020. Review. ISSN: 1043-6618. FI 2015816
  2. THE TRYPANOCIDAL BENZNIDAZOLE PROMOTES ADAPTIVE RESPONSE TO OXIDATIVE INJURY: INVOLVEMENT OF THE NUCLEAR FACTOR-ERYTHROID 2-RELATED FACTOR-2 (Nrf2) AND MULTIDRUG RESISTANCE ASSOCIATED PROTEIN 2 (MRP2). Rigalli JP, Perdomo VG, Ciriaci N, Francés DE, Ronco MT, Bataille AM, Ghanem CI, Ruiz ML, Manautou JE, Catania VA. Toxicol Appl Pharmacol. 2016 304:90-8. DOI: 10.1016/j.taap.2016.05.007. ISSN-0041-008X. FI2015847
  3. REGULATION OF MULTIDRUG RESISTANCE PROTEINS BY GENISTEIN IN A HEPATOCARCINOMA CELL LINE. IMPACT ON SORAFENIB CYTOTOXICITY. Rigalli JP, Ciriaci N, Arias A, Cevallos MP, Villanueva SM, Luquita M, Mottino AD,Ghanem CI, Catania VA, Ruiz ML. PLOS ONE. 2015. 10:e0119502. ISSN-1932-6203. FI2013353
  4. FRUCTOSE-INDUCED METABOLIC SYNDROME DECREASES PROTEIN EXPRESSION AND ACTIVITY OF INTESTINAL P-GLYCOPROTEIN. A Novak, YC Godoy; SA Martinez; CI Ghanem, SM Celuch, Nutrition. 2015. 31:871-6. DOI information: 10.1016/j.nut.2015.01.003. ISSN: 0899-9007. FI 2013046
  5. ROLE OF NUCLEAR FACTOR-ERYTHROID 2-RELATED FACTOR 2 (Nrf2) IN THE TRANSCRIPTIONAL REGULATION OF BRAIN ABC TRANSPORTERS DURING ACUTE ACETAMINOPHEN (APAP) INTOXICATION IN MICE. Ghanem CI,Rudraiah S, Bataille AM, Vigo MB, Goedken MJ, Manautou JE. Biochem Pharmacol. 2015. 94:203-11. doi:10.1016/j.bcp.2015.01.013. ISSN: 0006-2952. FI 2013772
  6. DIFFERENTIAL EFFECTS OF ENVIRONMENT-INDUCED CHANGES IN BODY TEMPERATURE ON MODAFINIL’S ACTIONS AGAINST METHAMPHETAMINE-INDUCED STRIATAL TOXICITY IN MICE.» Raineri M., Gonzalez B., Rivero Echeto C., Muñiz JA,. Ghanem CI, Cadet JL, García-Rill E, Urbano FJ, Bisagno V. Neurotoxicity Research.  27: 71-83. DOI 10.1007/s12640-014-9493-9.
  7. THE EFFECT OF ACETAMINOPHEN ON THE EXPRESSION OF ABCG2 IN TROPHOBLAST CELLS IMPAIRS THE PLACENTAL BARRIER TO BILE ACIDS DURING MATERNAL CHOLESTASIS. Blazquez AG, Briz O, Gonzalez-Sanchez E, Perez MJ, Ghanem CI,Marin JJ. Toxicology and Applied Pharmacology. 2014, 277:77-85.
  8. Acetaminophen inhibits intestinal P-glycoprotein transport activity. Novak A, Delli Carpini G, Ruiz ML, Luquita M, Rubio MC, Mottino AD, Ghanem CI. 2013. J Pham Sci 102:3830-7.
  9. ACETAMINOPHEN-INDUCED STIMULATION OF MDR1 EXPRESSION AND ACTIVITY IN RAT INTESTINE AND IN LS 174T HUMAN INTESTINAL CELL LINE. Ghanem CI, Arias A, Novak A, Carpini GD, Villanueva S, Blazquez AG, Marin JJ, Mottino AD, Rubio MC. Biochem Pharmacol. 81:244-250.

FUNDINGS

  • Research member. “La proteína de resistencia a multidrogras tipo 4, MRP4/ABCC4, como nuevo blanco terapéutico en carcinomas ductales pancreáticos humanos”. ($ 338.000). Director: Dr. Carlos Universidad de Buenos Aires- UBACYT-20020170100674BA (2018-2021).
  • Research Member. “Abordaje interdisciplinario para el desarrollo y optimización de aplicaciones farmacológicas en terapias dirigidas acáncer de páncreas y de vesícula biliar y vías biliares: validación de blancos terapéuticos, diseño y optimización racional de fármacos». Proyecto de Unidades Ejecutoras-CONICET. Director: Carlos Davio. 2017-2022. ($ 5.000.000).
  • Research Member. “Regulación de transportadores ABC intestinales por genisteína y su implicancia en la función de barrera química intestinal. Potencial aplicabilidad terapéutica en patologías que cursan con inflamación intestinal. Directora: Dra. Viviana A. Catania. Investigadores Responsables: Dres. Aldo D. Mottino, Silvina S. M. Villanueva, Carolina I. Ghanem y María L. Ruiz. PIP CONICET (112-2015-01-00202): ($ 585.000).

COLLABORATIONS

Internationals

  • JJG Garcia Marín. Hepatología experimental y vectorización de fármacos; Departamento de Fisiología y Farmacología de la Universidad de Salamanca. Universidad de Salamanca. Salamanca, España.
  • Jose E Manautou. School of pharmacy. University of Connecticut, Connecticut. USA.

Nationals

  • Aldo Mottino, Investigador Superior, CONICET. Instituto de Fisiología Experimental (IFISE)-CONICET, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario.
  • Viviana Catania, Investigador Independiente, CONICET. Instituto de Fisiología Experimental (IFISE)-CONICET, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario.
  • María Laura Ruiz, Investigador Asistente CONICET. Instituto de Fisiología Experimental (IFISE)-CONICET, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario.