Inhibición de lipasa pancreática por flavonoides: importancia del doble enlace C2=C3 y la estructura plana del anillo C//Inhibition of pancreatic lipase by flavonoids: relevance of the C2=C3 double bond and C-ring planarity

Abstract

Lipasa pancreática es una enzima clave en el metabolismo de lípidos. Los flavonoides son compuestos bioactivos de gran relevancia debido a sus interacciones con enzimas digestivas. Se evaluó la actividad de lipasa pancreática en presencia de flavonoides. Mediante espectroscopía UVVisible se determinó que el mejor inhibidor fue quercetina, seguido de rutina > luteolina > catequina > hesperetina, con valores de IC50 de 10.30, 13.50, 14.70, 28.50 y 30.50 μM, respectivamente. Todos los flavonoides mostraron una inhibición mixta, excepto catequina que mostró una inhibición acompetitiva. La capacidad inhibitoria de los flavonoides se relacionó con propiedades estructurales compartidas entre los distintos flavonoides, como la hidroxilación en las posiciones C5, C7 (anillo A), C2’ y C3’ (anillo B), y el doble enlace entre C2 y C3 (anillo C). Los resultados de inhibición coincidieron con el análisis de la fluorescencia extrínseca. Los estudios de docking molecular indicaron que la interacción entre lipasa pancreática y los flavonoides fue principalmente mediante interacciones hidrofóbicas (pi-stacking). Las interacciones de todos los flavonoides, excepto rutina, se dieron en el mismo sitio (subsitio 1) de la enzima. La insaturación entre C2 y C3 fue determinante para el acomodo de los flavonoides con la enzima, principalmente por interacciones de pi-stacking.ABSTRACTPancreatic lipase is a key enzyme in lipid metabolism. Flavonoids are bioactive compounds obtained from vegetables with big relevance, due to their intrinsic interaction with digestive enzymes. Pancreatic lipase activity was evaluated in the presence of flavonoids, through UV-Vis spectroscopy. All tested flavonoids showed a mixed-type inhibition, except catechin, which showed a uncompetitive inhibition. The best inhibitor was quercetin followed by rutin > luteolin > catechin > hesperetin, with IC50 values of 10.30, 13.50, 14.70, 28.50 and 30.50 μM, respectively. The flavonoids inhibitory capacity was related to structural properties shared between the different flavonoids, such as the hydroxylation at C5, C7 (ring A), C2’ and C3’ (ring B), and the double bond between C2 and C3 (ring C). The inhibition results are in agreement with the extrinsic fluorescence analysis. Molecular docking studies indicated that the interaction between pancreatic lipase and flavonoids was mainly through hydrophobic interactions (pi-stacking). The interactions of all flavonoids, except rutin, occurred at the same enzyme site (subsite 1). Instauration between C2 and C3 was decisive for the arrangement of flavonoids with the enzyme, mainly due to pi-stacking interactions.

Dietary Luteolin: A Narrative Review Focusing on Its Pharmacokinetic Properties and Effects on Glycolipid Metabolism

“…Besides the effect of luteolin on insulin secretion via the parasympathetic nervous system that was mentioned previously, , evidence supports the existence of a direct effect of luteolin on pancreatic β cells. ,, An inhibition of luteolin on pancreatic lipase activity (a key enzyme in lipid metabolism) with a low IC 50 value (13.50 μmol/L) has been found via ultraviolet–visible (UV–vis) spectroscopy . In diabetic rats, the pancreatic islet morphology and pancreatic glucose-6-phosphate dehydrogenase (G6PDH) activity can be improved with bioflavonoids, such as luteolin, luteolin 7- O -β-glucoside, and luteolin 7- O -β-glucuronoside .…”

“…78,114,115 An inhibition of luteolin on pancreatic lipase activity (a key enzyme in lipid metabolism) with a low IC 50 value (13.50 μmol/L) has been found via ultraviolet−visible (UV−vis) spectroscopy. 116 In diabetic rats, the pancreatic islet morphology and pancreatic glucose-6-phosphate dehydrogenase (G6PDH) activity can be improved with bioflavonoids, such as luteolin, luteolin 7-O-βglucoside, and luteolin 7-O-β-glucuronoside. 117 Moreover, immunohistochemistry staining of the pancreatic tissue for insulin and glucagon revealed that a 16 week treatment with luteolin could reverse HFD-induced pancreatic islet hypertrophy, leading to a decrease in pancreatic insulin and glucagon content, in accordance with the results obtained from plasma insulin and glucagon.…”

Aktivitas Inhibitor Lipase Ekstrak Daun Mangga Arum Manis dan Mangga Kweni Secara In Vitro

“…Selain itu, beberapa penelitian juga telah melaporkan bahwa senyawa flavonoid memiliki peranan penting dalam menghambat kerja lipase pankreas (Darusman et al, 2001;Zhao et al, 2009). Penelitian pada beberapa jenis senyawa flavonoid menunjukkan bahwa flavonoid dapat menghambat lipase melalui mekanisme penghambatan mixed-type inhibition (Martinez-Gonzaleza et al, 2020).…”