| Lipid is a kind of very important compounds in our body. It is based on the triglycerides or sphingol as skeleton, combined with hydrophilic substituent group containing phosphate and hydrophobic fatty acid chains. According to the different substituting of phosphoric acid and the diversification of fatty acid chain constitutes the different kinds of phospholipid compounds. On the basis of different skeleton, phospholipids can be divided into glycerol phospholipid and sphingomyelin. Glycerol phospholipid is divided into: phosphatidylcholines(PC), lysophosphatidylcholines(LPC), phosphatidyl inositol(PI), phosphatidyl ethanolamine(PE), phosphatidylserine(PS), in line with the different of the head. As we all known, lecithin are closely related to signal transduction, energy metabolism and anchored protein in cells. Currently phospholipids metabolic disorders and many diseases are closely related. Such as metabolic syndrome, diabetes, cerebral infarction, high blood pressure, etc. It is reported that lipids can also affect the drug metabolic enzymes. For example, phosphatidyl choline and lysophosphatidylcholines can influence the activity of cytochrome P450 enzymes(CYPs). Unsaturated fatty acid can inhibit renal UDP-glucuronosyltransferases enzymes(UGTs).Conjugation of compounds by glucuronidation has been demonstrated in all vertebrates. UGT is anchored at its C-terminal to the endoplasmic reticulum membrane, and the main body, including the catalytic domain, is located within the endoplasmic reticulum. As an important exogenous substances and drug metabolism enzymes, their catalytic glucuronic acid combination reactions take about 35% of all phase II drug metabolism. Many important clinical drug metabolic clearance depend on UGTs family. SN-38, the active intermediate of irinotecan, is main metabolized by UGT1A1. Non-steroid anti-inflammatory drug add glucose aldehyde acid are metabolited by UGT2B15 and UGT2B7. In addition, the metabolism of endogenous substance is also an important function of UGT enzymes. UGT1A1 catalyzes bilirubin metabolism, drugs to inhibit the activity of the UGT1A1 can lead to high blood bilirubin. The metabolisms of some hormones also need UGT enzymes to terminate activity and function. Some pathological conditions, UGT enzymes can detoxicate the toxic metabolite and facilitate clearance. In biliary obstruction, UGT enzymes facilitate all kinds of bile acid clearance. Therefore UGT enzymes for endogenous substance metabolism and remove are important factors to maintain the body’s internal environment stable.UGT enzymes activity can be inhibited by endogenous substances when they metabolize endogenous substance. For example, we have reported human bile acid can inhibit UGT enzyme. This study focused on another kinds of endogenous substances, phospholipids series compounds, inhibit to UGT enzymes. We investigates the inhibition of phospholipid class series compounds towards UGTs enzymes and evaluate the inhibitory kinetics of some have strong inhibitory effect. We found many lysophosphatidylcholines and phosphatidylcholines had strong inhibitory effect to UGTs enzymes, especially the lysophosphatidylcholines have broader UGTs enzyme inhibition. Phospholipid compounds are most likely to affect UGT1A6 and UGT1A8, two important UGT enzymes. UGT1A6 can metabolize serotonin; can also metabolic benzopyrene compounds in tobacco, its activity associated with the occurrence of lung cancer. UGT1A8 metabolize thyroid and estrogen. UGT1A8 is one of the gut expressions UGT enzymes involved in the body metabolism of exogenous substances as first barrier. Phospholipid ingredients as a kind of nutrient, excessive intake may affect UGT1A6 and UGT1A8 involved metabolic processes in the body.To clarify the mechanism of lysophosphatidylcholines inhibition to UGTs, we use protein homology model built protein crystal structure of the UGT1A6, and evaluate LPCs that have different chain length fatty acids combined with UGT1A6 using the molecular docking method. We found that the longer LPCs tend to occupy the whole cavity by situating the head inside the inner area while the tail of alkane towards the entrance of the pocket that keeps off the uridine diphosphate glucose access to UGTs, but the shorter cannot do. This is probably the mechanism of LPCs inhibition to UGT enzymes. |
