Lytic reactions of drugs with lipid membranes

Abstract

The involvement of drugs in direct chemical reactions with lipids may be linked to toxic effects in liver cell lines.

Far from Inert: Membrane Lipids Possess Intrinsic Reactivity That Has Consequences for Cell Biology

“…However, all of these limitations are mitigated by recent data obtained from a study of drug reactivity in both model and cell membranes where, at physiologically relevant concentrations, similar product profiles were found in vitro and in cellulo in Hep G2 cells. [4] In this work it was found the drug propranolol undergoes lipidation predominantly on the central hydroxyl group in a process that is formally a transesterification reaction with the lipid (Figure 3). The predominant products detectable in Hep G2 cells after 24 h are propranolol modified with the following acyl chains: C16:0 > C18:1 > C18:0 > C16:1 ≈C14:0, with C18:2, C20:1, C20:2, C20:3, C20:4, and C22:6 fatty acyl modifications also detectable as minor products.…”

“…For example, in the propranolol study, there is some evidence that the relative abundance of plasmalogens was increased in Hep G2 cells after administration of propranolol. [4] 2) Detection of lipidated products is challenging due to the diversity of products formed, combined with the likelihood of an incomplete reaction. In many cases, lipidated products evade detection because they are insoluble or elute in the wash phase at the end of a proteomics run.…”

Lysis of membrane lipids promoted by small organic molecules: Reactivity depends on structure but not lipophilicity

“…Agents that are capable of binding to membranes fall into one of two categories: Either they have no effect on lipid stability, or they are Compounds that induce lysolipid formation have also been linked with idiosyncratic toxic effects in vivo such as drug-induced phospholipidosis (13,14). It is likely, therefore, that many agents that affect lipid stability have similar activity.…”

“…The reactivity of propranolol is of particular significance as it extends the observation of acyl transfer to low-molecular weight species, suggesting that membranes may be far more reactive than previously thought. It is currently still not clear how general this reactivity is, however, as other molecules, including fluoxetine, sertraline, chloroquine (13), haloperidol, spiperone (14), and raclopride (15), have been shown to promote the formation of lysolipids in model systems by hydrolysis ( Fig. 1) without undergoing concurrent lipidation.…”

“…All the molecules described above that undergo lipidation reactions or influence the rate of lipid hydrolysis have a significant affinity for lipid membranes, and it is therefore not clear whether the reactivity will extend to lower-molecular weight species with much lower membrane affinity. Demonstration of such activity would not only change fundamental thinking on lipid membrane stability but also have additional implications for our understanding of membrane biology as there is some indication that lytic activity is responsible for downstream effects in vivo (13). Both the fatty acids and the lysolipids formed by these processes have substantial effects on membrane properties at abundance levels as low as 1 mol % due to their noncylindrical shape (16).…”