Hypolipidaemic drugs are activated to acyl-CoA esters in isolated rat hepatocytes: Detection of drug activation by human liver homogenates and by human platelets

M. Bronfman, M. N. Morales, L. Amigo, A. Orellana, L. Nunez, L. Cardenas, P. C. Hidalgo

Resultado de la investigación: Contribución a una revistaArtículorevisión exhaustiva

42 Citas (Scopus)

Resumen

The formation of acyl-CoA esters of the hypolipidaemic peroxisome proliferators clofibric acid, ciprofibrate and nafenopin was studied in isolated rat hepatocytes. The concentration of ciprofibroyl-CoA in the liver of ciprofibrate-treated rats was in the range of 10-30μM. The three drugs formed acyl-CoA esters when incubated with isolated hepatocytes. Their formation was saturable and reached a plateau after 30 min incubation. Maximal intracellular concentrations of ciprofibroyl-CoA and clofibroyl-CoA (100μM and 55μM respectively) were attained at 0.5mM of the free drugs in the incubation medium, whereas for nafenopin-CoA, the maximal intracellular concentration (9μM) was reached at 1mM-nafenopin. At low concentrations of the hypolipidaemic compounds in the incubation medium a significant proportion of the total intracellular drug was present as its acyl-CoA ester (25-35% for ciprofibrate). When isolated hepatocytes were incubated with a ciprofibrate concentration comparable with that observed in the blood of drug-treated rats (0.1mM), ciprofibroyl-CoA attained an intracellular concentration similar to that previously observed in the liver of treated rats. The formation of ciprofibroyl-CoA by isolated rat hepatocytes was stimulated by the addition of carnitine and partially inhibited by the addition of palmitate. Further, it was shown that human liver homogenates synthesized ciprofibroyl-CoA at a rate similar to that observed for rat liver homogenates. Solubilized human platelets also formed ciprofibroyl-CoA, although at a rate two orders of magnitude lower than that of liver. The results support the view that acyl-CoA esters of hypolipidaemic peroxisome proliferators may be the pharmacologically active species of the drugs.

Idioma originalInglés
Páginas (desde-hasta)289-295
Número de páginas7
PublicaciónBiochemical Journal
Volumen284
N.º1
DOI
EstadoPublicada - 1992

Áreas temáticas de ASJC Scopus

  • Bioquímica
  • Biología molecular
  • Biología celular

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