Deciphering biomembrane photodamage:Alkylation of a type I sensitizer enhances the photo-induced oxidation of phospholipid membranes

ANDRÉS H. THOMAS

Congreso; 19th Congress of the European Society for Photobiology; 2021

European Society for Photobiology

Pterins are endogenousphotosensitizers present in human skin that accumulate in this tissue in patientssuffering from vitiligo, a skin disorder characterized by the acquired loss ofconstitutional pigmentation. Experiments using model biological targets, suchas nucleotides and amino acids, have demonstrated that mainly act through typeI mechanism. These processes are initiated by a dynamic reaction, controlled bydiffusion, in which an electron transfer from the substrate to the tripletexcited state of the photosensitizer takes place. All unsaturated lipids in cellmembranes are well-known targets of oxidative damage, which can occur by type Iand type II photosensitized oxidation. In the case of vesicles dispersions, ahydrophilic photosensitizer will remain in the aqueous phase and thephotosensitized oxidation of a target molecule in the membrane will be adynamic process. On the other hand, if the photosensitizer is lipophilic, anassociation with a biomembrane is expected and, as the photosensitization isnot limited by diffusion, the oxidation might be much faster.Pterin (Ptr), the parent and model compound of oxidized pterins, is hydrophilic, does not bind tophospholipid membranes and, therefore, freely crosses biomembranes. Ptrphotoinduces the oxidation of polyunsaturated fatty acids (PUFAs) ofphospholipids present in large unilamellar vesicles (LUVs),predominantly through type I mechanism.1 Moreover, uponUVA irradiation in the presence of Ptr, the viability of HeLa cells decreases and the structural integrity of the cellmembrane are affected. In short, although Ptr remains in bulk water, it is ableto photoinduce membrane damage in simple model systems (LUVs), as well as ineukaryotic cells.In thesearch of better compounds that retain the photosensitizing properties ofpterins and, at the same time, are able to bind to biomembranes, a series ofdecyl-pterin derivatives were synthesized.2Amongthem, due to its photochemical properties (efficient intersystem crossing),4-(decyloxy)pteridin-2-amine (O-decyl-Ptr)was chosen for further studies using phospholipid membranes with variouscompositions. Conjugation of a decyl chain to thepterin moiety enables its facile intercalation in LUVs. In particular, O-decyl-Ptris positioned right between the polar head and the beginning of the fatty acidchains.3 Upon UVA irradiation lipid peroxidation photosensitized by O-decyl-Ptr leads to the formation ofhydroxyl derivatives, hydroperoxides and hydroxyhydroperoxides.4 Thesephotoproducts undergo a fast conversion into short-chain secondary products bycleavage of the fatty acid chains most likely due to further photosensitizedprocesses. These short-chain oxidized lipids are responsible for destabilizingthe phospholipid bilayer and promoting membrane leakage. The efficiency ofphotodamage, assessed in terms of oxidized products formation rate and membranepermeabilization, is much higher for O-decyl-Ptr than forfree Ptr,4 which indicates that the intercalation of the alkyl-pterin to themembrane enhances the photosensitized reactions. O-decyl-Ptr is also much moreefficient than Ptr in the photodynamic activity on HeLa cells.3 References1) A. H. Thomas, A. Catalá, M.Vignoni, Soybean phosphatidylcholine liposomes as model membranes to studylipid peroxidation photoinduced by pterin, Biochim.Biophys. Acta 1858 (2016) 139?145.2) M. Vignoni, N. Walalawela,S. M. Bonesi, A. Greer, A.H. Thomas, Lipophilic decyl chain-pterin conjugateswith sensitizer properties, Mol. Pharm. 15 (2018) 798-807.3) A. Vignoni, C. Layana, H.C.Junqueira, A.H. Thomas, R. Itri, M.S. Baptista, M. Vignoni, Alkylation of ahydrophilic photosensitizer enhances the contact-dependent photo-inducedoxidation of phospholipid membranes, DyesPigm. 187 (2021) 109131.4) M. Vignoni, M. N. Urrutia,H. C. Junqueira, A. Greer, A. Reis, M. S. Baptista, R. Itri, A .H. Thomas,Photo-Oxidation of unilamellar vesicles by a lipophilic pterin: deciphering.biomembrane photodamage, Langmuir 34(2018) 15578-15586.