Page 131 - 83_02
P. 131
que no puede ser conjugado, se secreta en la bilis, se 11. Ramachandran R, Kakar S. Histological patterns in
reabsorbe por los colangiocitos y vuelve al hígado. Esta drug-induced liver disease. Journal of clinical
circulación cole-hepática conduce a un aumento de pathology 2009;62:481-492.
bicarbonato en la bilis e induce hipercoleresis. De este
modo, el norUDCA revierte la colangitis esclerosante en el 12. Begriche K, Massart J, Robin MA, Borgne-Sanchez A,
modelo Mdr2-/- (ABCB4) de colangiopatía (73). Por Fromenty B. Drug-induced toxicity on mitochondria
último, el ácido obeticolico (OCA, 6ethyl-CDCA o INT- and lipid metabolism: mechanistic diversity and
747) es un agonista potente y selectivo del FXR (74). En deleterious consequences for the liver. Journal of
estudios con animales, el OCA aumenta la sensibilidad a la hepatology 2011;54:773-794.
insulina, inhibe la gluconeogénesis, inhibe la lipogénesis, y
también tiene propiedades anti-inflamatorias y anti- 13. Aires CC, Ijlst L, Stet F, Prip-Buus C, de Almeida IT,
fibróticas (74). En estudios clínicos de pacientes con CBP, Duran M, et al. Inhibition of hepatic carnitine
el OCA redujo significativamente la ALP. Sin embargo, la palmitoyl-transferase I (CPT IA) by valproyl-CoA as
mayoría de los pacientes desarrollaron prurito, un síntoma a possible mechanism of valproate-induced steatosis.
común de la colestasis y un efecto secundario habitual en Biochemical pharmacology 2010;79:792-799.
las terapias con AB (73).
14. Fromenty B, Pessayre D. Inhibition of mitochondrial
3. CONCLUSIONES beta-oxidation as a mechanism of hepatotoxicity.
Pharmacology & therapeutics 1995;67:101-154.
La esteatosis y la colestasis por fármacos son el
resultado de múltiples mecanismos, siendo la alteración de 15. Donato MT, Gomez-Lechon MJ. Drug-induced liver
la regulación transcripcional una vía potencial adicional steatosis and phospholipidosis: cell-based assays for
que debe investigarse, ya que permitiría un mejor early screening of drug candidates. Current drug
conocimiento de la hepatotoxicidad y la posibilidad de metabolism 2012;13:1160-1173.
desarrollar nuevas herramientas diagnósticas que
complementen a las actuales. 16. Letteron P, Sutton A, Mansouri A, Fromenty B,
Pessayre D. Inhibition of microsomal triglyceride
4. BIBLIOGRAFÍA transfer protein: another mechanism for drug-induced
steatosis in mice. Hepatology 2003;38:133-140.
1. Canbay A, Bechmann L, Gerken G. Lipid metabolism
in the liver. Z Gastroenterol 2007;45:35-41. 17. Amacher DE. The mechanistic basis for the induction
of hepatic steatosis by xenobiotics. Expert opinion on
2. Kawano Y, Cohen DE. Mechanisms of hepatic drug metabolism & toxicology 2011;7:949-965.
triglyceride accumulation in non-alcoholic fatty liver
disease. Journal of gastroenterology 2013;48:434-441. 18. Lee MH, Hong I, Kim M, Lee BH, Kim JH, Kang KS,
et al. Gene expression profiles of murine fatty liver
3. Cohen JC, Horton JD, Hobbs HH. Human fatty liver induced by the administration of valproic acid.
disease: old questions and new insights. Science Toxicology and applied pharmacology 2007;220:45-
2011;332:1519-1523. 59.
4. Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: 19. Lee MH, Hong I, Kim M, Lee BH, Kim JH, Kang KS,
from steatosis to cirrhosis. Hepatology 2006;43:S99- et al. Gene expression profiles of murine fatty liver
S112. induced by the administration of methotrexate.
Toxicology 2008;249:75-84.
5. Kim CH, Younossi ZM. Nonalcoholic fatty liver
disease: a manifestation of the metabolic syndrome. 20. Lee MH, Kim JW, Kim JH, Kang KS, Kong G, Lee
Cleveland Clinic journal of medicine 2008;75:721- MO. Gene expression profiling of murine hepatic
728. steatosis induced by tamoxifen. Toxicology letters
2010;199:416-424.
6. Marchesini G, Marzocchi R, Agostini F, Bugianesi E.
Nonalcoholic fatty liver disease and the metabolic 21. Lee MH, Kim M, Lee BH, Kim JH, Kang KS, Kim
syndrome. Current opinion in lipidology 2005;16:421- HL, et al. Subchronic effects of valproic acid on gene
427. expression profiles for lipid metabolism in mouse
liver. Toxicology and applied pharmacology
7. Ramesh S, Sanyal AJ. Hepatitis C and nonalcoholic 2008;226:271-284.
fatty liver disease. Seminars in liver disease
2004;24:399-413. 22. Yin HQ, Kim M, Kim JH, Kong G, Lee MO, Kang
KS, et al. Hepatic gene expression profiling and lipid
8. Larrain S, Rinella ME. A myriad of pathways to NASH. homeostasis in mice exposed to steatogenic drug,
Clinics in liver disease 2012;16:525-548. tetracycline. Toxicological sciences 2006;94:206-216.
9. Anstee QM, Daly AK, Day CP. Genetics of alcoholic 23. Benet M, Moya M, Donato MT, Lahoz A, Hervas D,
and nonalcoholic fatty liver disease. Seminars in liver Guzman C, et al. A simple transcriptomic signature
disease 2011;31:128-146. able to predict drug-induced hepatic steatosis.
Archives of toxicology 2014;88:967-982.
10. Grieco A, Forgione A, Miele L, Vero V, Greco AV,
Gasbarrini A, et al. Fatty liver and drugs. European 24. Lopez-Riera M, Conde I, Tolosa L, Zaragoza A,
review for medical and pharmacological sciences Castell JV, Gomez-Lechon MJ, et al. New microRNA
2005;9:261-263. Biomarkers for Drug-Induced Steatosis and Their
Potential to Predict the Contribution of Drugs to Non-
@Real Academia Nacional de Farmacia. Spain
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