Inhibitory effects of phenolic compounds on human lipase activity

Lipase plays an important role in lipid digestion, therefore by using of lipase inhibitors, fat absorption can be decreased and potentially result into weight loss. Phenolic compounds have been reported as lipase inhibitors. In this study, the effects of 14 phenolic compounds on lipase activity were examined. Our results showed that 4,4′-isopropylidenediphenol, bithionol, hexachlorophene, and diethylstilbestrol can be considered as a lipase inhibitor, while diethylstilbestrol has the highest inhibitory effect on lipase. Human lipase (LPS) is a single-chain glycoprotein with 449 amino acids and a molecular weight of 52 KD that hydrolyze glycerol esters of triacylglycerols LPS can be inhibited by various natural and chemical compounds In this research, the inhibitory effect of phenolic compounds have been investigated on LPS. In this in vitro study we analyzed the effect of these 14 compounds on lipase activity: 2,6-Diisopropylphenol, 3,5-Diiodosalicylic acid, Carvacrol, 4-Chloro-2-isopropyl-5-methylphenol Cumylphenol, Bithionol, Bis(4-hydroxyphenyl) methane, 4,4′-Cyclohexylidenebisphenol, Diethylstilbestrol, Diflunisal, 4,4′-Isopropylidenediphenol, 4,4′-Isopropylidenebis(2,6-dimethylphenol), Hexachlorophene and Tolmetin. All these compound purchased from Sigma (ST Louis USA). Dimethylsulfoxide (DMSO) (Merck/Darmstadt/Germany) was used as a solvent for the preparation of different concentrations (65, 325, 650, 3250 mMOL) of above-mentioned compounds. Lipase activity was measured in normal (Trulab N) and pathologic (Trulab P) control sera using the commercial kit (Pars azmun,Tehran, Iran) and automated chemistry analyzer ( Hitachi 902 Made in Japan ) before and after addition of each prepared solutions to kit’s reagent. The pdb format compounds were downloaded from zinc.docking.org and docked into LPS structure (1LPB pdb) with the use of www.swissdock.ch and the result wasanalyzed by UCSF chimera 1.11rc, LIGPLOT⁺ , and PYMOL. Our results showed that double- ring phenolic compounds have a stronger capability to inhibit LPS than compounds with one ring which may be due to the increased number of phenolic hydroxyl groups. In double- ring phenolic compounds, the presence of chloride or methane groups (and also their number) can also influence the inhibitory effects. The overall results have been reported in table1. Few compounds with one ring such as 2,6-diisopropylphenol, 3,5-diiodosalicylic acid and 4-chloro-2-isopropyl-5-methylphenol had an activator effect on LPS. We found Lowest Delta G for the interactionof bithionol, hexachlorophene, 4,4′-isopropylidenediphenol and diethylstilbestrol with LPS. The maximum inhibitory effect was obtained by diethylstilbestrol. The highest number of hydrophobic and hydrogen bonds with LPS were found for bithionol and 4,4′-cyclohexylidenebisphenol respectively. For the best compounds hexachlorophene, 4,4′-isopropylidenediphenol and diethylstilbestrol, half maximal inhibitory concentration (IC50) was separately estimated for Trulab N and Trulab P using linear regression and the results were as follows: Diethylstilbestrol: 3.87 and 3.91 mMol, Hexachlorophene: 4.5 and 7.3 mMol,4,4′-Isopropylidenediphenol: 4.1 and 8.5 mMol. Using C11-alkyl-3- phosphonate as a well-known LPS inhibitor (5) for comparative means, we evaluated the potential amino acids involved in the interaction between LPS and diethylstilbestrol, hexachlorophene, bithionol, and 4,4′-isopropylidenediphenol. The results demonstrated that His263- Phe215- Phe77 and Gly76 are common amino acids in the reactiontoabove-mentioned compounds and LPS. The results of the present study showed that bithionol,hexachlorophene, 4,4′-isopropylidenediphenol,and diethylstilbestrol have an inhibitory effect on LPS. Among them, diethylstilbestrol is the most powerful inhibitor with 3 hydrogen bonds, 15 hydrophobic bonds, delta G (-8.2) and 41% of LPS inhibition. The second one is 4,4′-isopropylidenediphenol with 4 hydrogen bonds, 13 hydrophobic bonds, delta G (-7.5) and 33% of LPS inhibition. In third place, we have hexachlorophene with 16 hydrophobic bonds, delta G (-8.3) and 32% of LPS inhibition and the last one is bithionol with 21 hydrophobic bonds, delta G (-8.0) and 23% of LPS inhibition.

کلیدواژه ها:

Lipase ، Inhibitor ، Phenolic compound