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 Fenofibrate -a PPARα agonist- increases alcohol dehydrogenase levels in the liver: implications for its possible use as an ethanol-aversive drug

Autores/as

  • Daniel Muñoz Instituto de Ciencias Biomédicas Facultad de Ciencias de la Salud
  • Mario Rivera-Meza Universidad de Chile
  • Osvaldo Flores-Bastías Instituto de Ciencias Biomédicas. Facultad de Ciencias de la Salud. Universidad Autónoma de Chile
  • María Elena Quintanilla Universidad de Chile
  • Eduardo Karahanian Instituto de Ciencias Biomédicas Facultad de Ciencias de la Salud Universidad Autónoma de Chile

DOI:

https://doi.org/10.20882/adicciones.1226

Palabras clave:

Fibrato, Receptor activado por proliferadores de peroxisomas, PPAR, Alcohol deshidrogenasa, Tratamiento trastorno por uso de alcohol. Fibrate, Peroxisome proliferator-activated receptor, PPAR, Alcohol dehydrogenase, Alcohol use disorder treatment.

Resumen

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. 
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 high-drinker 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. 

Biografía del autor/a

Daniel Muñoz, Instituto de Ciencias Biomédicas Facultad de Ciencias de la Salud

Institute of Biomedical Sciences, Faculty of Health Sciences, Universidad Autónoma de Chile, Santiago, Chile. 

Mario Rivera-Meza, Universidad de Chile

Departamento de Química Farmacológica y Toxicológica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile

Osvaldo Flores-Bastías, Instituto de Ciencias Biomédicas. Facultad de Ciencias de la Salud. Universidad Autónoma de Chile

Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud.Centro de Investigación para el Estudio de la Conducta del Consumo de Alcohol en Adolescentes, Universidad Autónoma de Chile, Santiago, Chile.

María Elena Quintanilla, Universidad de Chile

Programa de Farmacología Molecular y Clínica, Facultad de Medicina, Instituto de Ciencias Biomédicas, Universidad de Chile, Santiago, Chile.

Eduardo Karahanian, Instituto de Ciencias Biomédicas Facultad de Ciencias de la Salud Universidad Autónoma de Chile

Académico-InvestigadorInstituto de Ciencias Biomédicas

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Publicado

2019-03-29

Número

Vol. 32 Núm. 3 (2020)

Sección

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