Terpenes and cell membranes

Terpene and lipid interactions: Not uncharted territory

Terpene interactions with phospholipids in cell membranes and how those phospholipids communicate with receptors in those membranes is a bit of an unknown. However…. We already know more than we may realize just from the history of terpene use as transdermal permeablity enhancers.

Trans dermal delivery of drugs through the stratum corneum may occur via one of three routes (1) through skin appendages, (2) through keratin filled dead corneocytes, or (3) through extracellular lipids. The lipids, comprised of 50% ceramides, 25% cholesterol, 15% free fatty acids, as well as low levels of phospholipids . This Chen review becomes relevant to CB1 in that ceramides are also found in lipid rafts in which CB1 resides. These ceramides are arranged in stratum corneum bilayers with stabilizing hydrogen bonding. Terpenes are proposed to weaken this hydrogen bonding network by competing for ceramide/ceramide couplings. ATR FITR studies were cited in the Chen review. Linear monoterpene nerolidol was found to have the highest level of disruption compared to camphor, and menthol.

Part of the discussion of the Chen [1] review proposed that terpene loosening the hydrogen bonding of the ceramide barrier was one element of enhanced transdermal drug delivery. Another element is terpene-drug interactions: H-bond donor/acceptor interactions, van der Waals forces, and π-interactions. [1]

Terpenes and lipid bilayer phase transitions

Like water, lipid bilayers have phases. This particular image of a sterol interacting with is from UC Davis. The Royal Society also has an interesting take on the role of cholesterol in lipid bilayers. Here T_m and T_c both refer to the temperature inat whcih a phase transition occurs,. By analogy T_m for H₂O is 0^oC. Pham et al study considered three phases of dimyrisotoly phosphatidyl choline [3] stated in their introduction that in hydrated conditions

• < 15 °C planar Lβ′ gel phase with solid chains
• , and a rippled Pβ gel phase at intermediate temperatures.
• > 24 °C, side chains are fluid, Lα.

This group used differential scanning calorimetry to detect phase transition temperatures and solid state NMR of ¹H−¹³C polarization to assess acyl chain dynamics. The results showed that terpenes only minor effects on lipid dynamics, bulky thymol more than geraniol. [3] The hydroxyl group of thymol was predicted to be at the water lipid interface at at 10% molar percent. [3] These results are really not that surprising when an attempt is made to compare the sizes of thymol, geraniol, and cholesterol to a molecule of dimyistoylphsphatidylcholine.

References

1. Chen J, Jiang Q-D, Chai Y-P, Zhang H, Peng P,Yang X-X (2016) Natural Terpenes as Penetration Enhancers for Transdermal Drug Delivery Molecules 2016, 21, 1709
2. Moore DJ, Rerek ME. Insights into the molecular organization of lipids in the skin barrier from infrared spectroscopy studies of stratum corneum lipid models. Acta Derm Venereol Suppl (Stockh). 2000;208:16-22. free article
3. Pham QD, Topgaard D, Sparr E. (2015) Cyclic and Linear Monoterpenes in Phospholipid Membranes: Phase Behavior, Bilayer Structure, and Molecular Dynamics. Langmuir. 2015 Oct 13;31(40):11067-77.