Britt Hannah M, García-Herrero Clara A, Denny Paul W, Mosely Jackie A, Sanderson John M
Chemistry Department , Durham University , South Road , Durham , DH1 3LE , UK . Email:
Department of Biosciences , Durham University , Stockton Road , Durham , DH1 3LE , UK.
Chem Sci. 2018 Dec 3;10(3):674-680. doi: 10.1039/c8sc04831b. eCollection 2019 Jan 21.
Propranolol is shown to undergo lipidation reactions in three types of lipid membrane: (1) synthetic single-component glycerophospholipid liposomes; (2) liposomes formed from complex lipid mixtures extracted from or liver cells; and (3) in Hep G2 cells. Fourteen different lipidated propranolol homologues were identified in extracts from Hep G2 cells cultured in a medium supplemented with propranolol. This isolation of lipidated drug molecules from liver cells demonstrates a new drug reactivity in living systems. Acyl transfer from lipids to the alcoholic group of propranolol was favoured over transfer to the secondary amine. Migration of acyl groups from the alcohol to the amine was diminished. Other drugs that were examined did not form detectable levels of lipidation products, but many of these drugs did affect the lysolipid levels in model membranes. The propensity for a compound to induce lysolipid formation in a model system was found to be a predictor for phospholipidosis activity .
（1）合成单组分甘油磷脂脂质体；（2）从肝细胞中提取的复杂脂质混合物形成的脂质体；以及（3）在Hep G2细胞中。在补充有普萘洛尔的培养基中培养的Hep G2细胞提取物中鉴定出了14种不同的脂化普萘洛尔同系物。从肝细胞中分离出脂化药物分子证明了生物系统中的一种新的药物反应性。脂质向普萘洛尔醇基的酰基转移比向仲胺的转移更有利。酰基从醇向胺的迁移减少。所检测的其他药物未形成可检测水平的脂化产物，但其中许多药物确实影响了模型膜中的溶血脂质水平。发现化合物在模型系统中诱导溶血脂质形成的倾向是磷脂沉着症活性的一个预测指标。
