Fenofibrato -un agonista de PPARα- incrementa los niveles de la alcohol deshidrogenasa hepática: implicaciones para su posible uso como una droga de aversión al etanol

• Autores: Daniel Muñoz, Mario Rivera Meza, Osvaldo Flores Bastías, María Elena Quintanilla, E. Karahanian
• Localización: Adicciones: Revista de socidrogalcohol, ISSN 0214-4840, Vol. 32, Nº. 3, 2020, págs. 208-215
• Idioma: español
• Títulos paralelos:
  • Fenofibrate -a PPARα agonist- increases alcohol dehydrogenase levels in the liver: implications for its possible use as an ethanol-aversive drug
• Enlaces
  • Texto completo
• Resumen
  • español

    Tras consumir etanol, el disulfiram incrementa los niveles de acetaldehído en sangre y genera una reacción aversiva que desalienta el consumo de alcohol. Dados los importantes efectos secundarios del disulfiram, es altamente deseable hallar otros fármacos efectivos para tratar el trastorno por uso de alcohol. Se ha reportado que administrar fenofibrato a ratas altamente bebedoras de alcohol aumenta los niveles de catalasa hepática y acetaldehído en sangre después de la administración de etanol, y disminuye el consumo voluntario de alcohol (60-70%).

    Este trabajo evalúa si el fenofibrato tiene un efecto adicional sobre la actividad de otras enzimas en el metabolismo del etanol que podría contribuir a generar altos niveles de acetaldehído. Se permitió a ratas macho altamente bebedoras beber voluntariamente etanol 10% durante 2 meses. Después, se les administró oralmente fenofibrato (100 mg/kg/ día) o solo vehículo durante 14 días. Tras eso, se midieron los niveles hepáticos y actividades enzimáticas de alcohol deshidrogenasa (ADH1) y de aldehído deshidrogenasa (ALDH2). El fenofibrato produjo un marcado aumento en los niveles proteicos de ADH1 (396% ± 18%, p < ,001) y de actividad enzimática (425% ± 25%, p < ,001) sin alterar los niveles protéicos ni la actividad de ALDH2. Los resultados muestran que el tratamiento con fenofibrato no solo aumenta la actividad de catalasa en el hígado de ratas bebedoras de alcohol, sino que también incrementa los niveles y la actividad de ADH1, sin alterar ALDH2. Esto contribuye a explicar el notable efecto del fenofibrato en aumentar los niveles de acetaldehído en sangre en animales bebedores de alcohol, en los que se registra una marcada reducción en la ingesta de etanol.

  • English

    After ethanol consumption, disulfiram increases blood-acetaldehyde levels, generating an aversive reaction that deters alcohol drinking.

    Given the major secondary effects of disulfiram, finding other effective drugs to reduce alcohol consumption in individuals with alcohol-use-disorder is highly desirable. It has been reported that administering fenofibrate to high-drinking rats increases hepatic catalase levels and blood acetaldehyde after administering ethanol and a 60-70% inhibition of voluntary alcohol intake. This work evaluated whether fenofibrate has an additional effect on the activity of other ethanol-metabolizing enzymes, which could contribute to the high acetaldehyde levels generated upon administering ethanol. Male highdrinker rats were allowed to voluntary drink 10% ethanol or water for 2 months. Subsequently, fenofibrate (100 mg/kg/day) or vehicle was administered orally for 14 days. Then, alcohol dehydrogenase (ADH1) and aldehyde dehydrogenase (ALDH2) protein levels and enzymatic activities in the livers were quantified. Fenofibrate treatment produced a marked increase in ADH1 protein levels (396% ± 18%, p < 0.001) and enzymatic activity (425% ± 25%, p < 0.001). Fenofibrate did not result in differences in ALDH2 activity or in ALDH2 protein levels. The studies show that treatment with fenofibrate not only increased the activity of catalase in the liver of alcohol-drinking rats, as reported earlier, but also increased the levels and enzymatic activity of ADH1, while ALDH2 remained unchanged. The increases in ADH1 contribute to explaining the remarkable effect of fenofibrate in raising blood levels of acetaldehyde in ethanol-consuming animals, in which a marked reduction of alcohol intake is recorded

• Referencias bibliográficas
  • Badger, T. M., Hoog, J. O, Svensson, S., McGehee, R. E. Jr., Fang, C., Ronis, M. J. y Ingelman-Sundberg M. (2000). Cyclic expression of class...
  • Blednov, Y. A., Black, M., Benavidez, J. M., Stamatakis, E. E. y Harris, R.A. (2016). PPAR agonists: I. Role of receptor subunits in alcohol...
  • Christensen, J. K., Moller, I. W., Ronsted, P., Angelo, H. R. y Johansson, B. (1991). Dose-effect relationship of disulfiram in human volunteers....
  • Crabb, D. W., Pinaire, J., Chou, W.Y., Sissom, S., Peters, J.M., Harris, R. A. y Stewart, M. (2001). Peroxisome proliferator-activated receptors...
  • Deaciuc, I. V., Arteel, G. E., Peng, X., Hill, D. B. y McClain, C. J. (2004). Gene expression in the liver of rats fed alcohol by means of...
  • Dupuy, O., Flocard, F., Vial, C., Rode, G., Carles, N., Boisson, D. y Flechaire, A. (1995). Disulfiram toxicity. Le Revue de Medecine Interne,...
  • Faiman, M. D., Jensen, J. C. y Lacoursiere, R. B. (1984). Elimination kinetics of disulfiram in alcoholics after single and repeated doses....
  • Ferguson, L. B., Most, D., Blednov, Y. A. y Harris, R. A. (2014). PPAR agonists regulate brain gene expression: relationship to their effects...
  • Frye, R. F. y Branch, R. A. (2002). Effect of chronic disulfiram administration on the activities of CYP1A2, CYP2C19, CYP2D6, CYP2E1, and...
  • Gervois, P., Fruchart, J. C. y Staels, B. (2007). Drug Insight: mechanisms of action and therapeutic applications for agonists of peroxisome...
  • Haile, C. N. y Kosten, T. A. (2017). The peroxisome proliferator-activated receptor alpha agonist fenofibrate attenuates alcohol self-administration...
  • Handler, J. A. y Thurman, R. G. (1988a). Catalase-dependent ethanol oxidation in perfused rat liver. Requirement for fatty-acid-stimulated...
  • Handler, J. A. y Thurman, R. G. (1988b). Hepatic ethanol metabolism is mediated predominantly by catalase-H2O2 in the fasted state. FEBS Letters,...
  • He, L., Ronis, M. J. y Badger, T. M. (2002). Ethanol induction of class I alcohol dehydrogenase expression in the rat occurs through alterations...
  • Hellström, E. y Tottmar, O. (1982). Effects of aldehyde dehydrogenase inhibitors on enzymes involved in the metabolism of biogenic aldehydes...
  • Israel, Y., Rivera-Meza, M., Karahanian, E., Quintanilla, M. E., Tampier, L., Morales, P. y Herrera-Marschitz, M. (2013). Gene specific modifications...
  • Israel, Y., Quintanilla, M. E., Karahanian, E., Rivera-Meza, M. y Herrera-Marschitz, M. (2015). The “first hit” toward alcohol reinforcement:...
  • Karahanian, E., Ocaranza, P. y Israel, Y. (2005). Aldehyde dehydrogenase (ALDH2) activity in hepatoma cells is reduced by an adenoviral vector...
  • Karahanian, E., Quintanilla, M. E., Tampier, L., Rivera-Meza, M., Bustamante, D., Gonzalez-Lira, V., … Israel, Y. (2011). Ethanol as a prodrug:...
  • Karahanian, E., Quintanilla, M. E., Fernandez, K. y Israel, Y. (2014). Fenofibrate -a lipid-lowering drug- reduces voluntary alcohol drinking...
  • Karahanian, E., Rivera-Meza, M., Tampier, L., Quintanilla, M. E., Herrera-Marschitz, M. y Israel, Y. (2015). Long-term inhibition of ethanol...
  • Kramer, J. A., Blomme, E. A., Bunch, R. T., Davila, J. C., Jackson, C. J., Jones, P. F., … Curtiss, S. W. (2003). Transcription profiling...
  • Lee, S. L., Höög, J. O. y Yin, S. J. (2004). Functionality of allelic variations in human alcohol dehydrogenase gene family: assessment of...
  • Lieber, C. S. (1988). Pathophysiology of alcoholic liver disease. Molecular Aspects of Medicine, 10, 107-146. doi:10.1016/0098-2997(88)90018-0.
  • Maisel, N. C., Blodgett, J. C., Wilbourne, P. L., Humphreys, K. y Finney, J. W. (2013). Meta-analysis of naltrexone and acamprosate for treating...
  • Mark, T. L., Kranzler, H. R., Song, X., Bransberger, P., Poole, V. H. y Crosse, S. (2003). Physicians’ opinions about medications to treat...
  • Mays, D. C, Nelson, A. N., Fauq, A. H., Shriver, Z. H., Veverka, K. A., Naylor, S. y Lipsky, J. J. (1995). S-methyl N,N-diethylthiocarbamate...
  • Moffit, J. S., Koza-Taylor, P. H., Holland, R. D., Thibodeau, M. S., Beger, R. D., Lawton, M. P. y Manautou, J. E. (2007). Differential gene...
  • Quintanilla, M. E., Israel, Y., Sapag, A. y Tampier, L. (2006). The UChA and UChB rat lines: metabolic and genetic differences influencing...
  • Quintanilla, M. E., Tampier, L., Sapag, A., Gerdtzen, Z. y Israel, Y. (2007). Sex differences, alcohol dehydrogenase, acetaldehyde burst,...
  • Rivera-Meza, M., Quintanilla, M. E., Tampier, L., Mura, C. V., Sapag, A. y Israel, Y. (2010). Mechanism of protection against alcoholism by...
  • Rivera-Meza, M., Quintanilla, M. E. y Tampier, L. (2012). Reduction of ethanol consumption in alcohol-preferring rats by dual expression gene...
  • Rivera-Meza, M., Muñoz, D., Jerez, E., Quintanilla, M. E., Salinas-Luypaert, C., Fernandez, K. y Karahanian, E. (2017). Fenofibrate administration...
  • Sinclair, J. M. A., Chambers, S. E., Shiles, C. J. y Baldwin, D. S. (2016). Safety and tolerability of pharmacological treatment of alcohol...
  • Skinner, M. D., Lahmek, P., Pham, H. y Aubin, H. J. (2014). Disulfiram efficacy in the treatment of alcohol dependence: a meta-analysis. PLoS...
  • Thomasson, H. R., Edenberg, H. J., Crabb, D. W., Mai, X. L., Jerome, R. E., Li, T.K., … Yin, S. J. (1991). Alcohol and aldehyde dehydrogenase...
  • Thomasson, H. R., Crabb, D. W., Edenberg, H. J., Li, T. K., Hwu, H. G., Chen, C. C., … Yin, S. J. (1994). Low frequency of the ADH2*2 allele...
  • Tzeng, J., Byun, J., Park, J. Y., Yamamoto, T., Schesing, K., Tian, B., … Oka, S. (2015). An ideal PPAR response element bound to and activated...
  • Vidal, F., Perez, J., Morancho, J., Pinto, B. y Richart C. (1990). Hepatic alcohol dehydrogenase activity in alcoholic subjects with and without...
  • Yoshimura, A., Kimura, M., Nakayama, H., Matsui, T., Okudaira, F., Akazawa, S., … Higuchi, S. (2014). Efficacy of disulfiram for the treatment...