Antiobesity drug-likeness properties and pancreatic lipase inhibition of a novel low molecular weight lutein oxidized product, LOP6.

Abstract

Elevated expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ), a key regulator of adipogenesis, leads to lipid accumulation and obesity. Although orlistat is effective for obesity, flatus with discharge, faecal urgency, oily evacuation and other allied side effects limit its usage. Thus, natural product-based drug intervention is the future of research and development of novel treatment. We synthesized and characterized total lutein oxidized products (LOPs) by exposing lutein to direct sunlight with a solar intensity of 5.89 kW h m-2 day-1 and at 31 ± 2 °C for 1-10 days. Total LOPs were analyzed on C18 and structural elucidation was carried on LCMS/MS-TOF. The pancreatic lipase inhibition kinetics was estimated. The binding effects of LOP6 (fragmented peak 6) on PPAR-γ, pancreatic lipase, pharmacokinetic properties and inhibition studies were analysed. Histological evaluation of liver and adipose tissues was performed to confirm the antiobesity effect of total LOPs. The yield of extracted lutein purified from shade-dried marigold flower petals was 6%. Total LOPs were formed on the 10th day upon exposure of lutein to direct sunlight. Total LOPs on the C18 column fragmented into eight oxidized products (LOP1 to LOP8). The total LOPs showed significant inhibition of pancreatic lipase activity with an IC50 of 1.6953 μg ml-1, and Km and Vmax of 3.05 μg and 1.19 μg s-1 respectively following mixed type of inhibition. The LOP6 [4-((1E,3E,5E)-3,7-dimethylocta-1,3,5,7-tetraen-1-yl)-3,5,5-trimethylcyclohex-3-enol] with an approximate molecular mass of 274.25 showed a binding energy of -5.40 kcal mol-1 with a Ki of 109.43 μM for PPAR-γ and a docking score of -5.35 kcal mol-1 with a Ki of 119.4 μM for pancreatic lipase. The IC50 of LOP6 was 11.8420 μg ml-1, and Km and Vmax were 2.519 μg and 1.294 μg s-1. The pharmacokinetic properties such as solubility, permeability, bioavailability, and topological polar surface area when tested with LOP6 were significantly better than those of lutein alone. The histological examination of the liver and adipose tissue revealed that all three doses of total LOPs were effective in alleviating the ballooning and vesicular degeneration of hepatocytes and invasion of inflammatory cells in the adipose tissue. Total LOPs and LOP6 inhibited pancreatic lipase activity in vitro. LOP6 showed a better docking score for PPAR-γ and pancreatic lipase in comparison to orlistat. Histological data showed that the total LOPs exerted antiobesity activity. Thus, LOPs might provide a novel treatment approach for obesity.