Potential phototoxicity of rosuvastatin mediated by its dihydrophenanthrene-like photoproduct.

Abstract

In this work, rosuvastatin has been used to gain insight into the molecular basis of statin photosensitization. This lipid-lowering drug, also known as "superstatin", contains a 2-vinylbiphenyl-like moiety and has been previously described to decompose under solar irradiation, yielding stable dihydrophenanthrene analogues. During photophysical characterization of rosuvastatin, only a long-lived transient at ca. 550 nm was observed and assigned to the primary photocyclization intermediate. Thus, the absence of detectable triplet-triplet absorption and the low yield of fluorescence rules out the role of the parent drug as an efficient sensitizer. In this context, the attention has been placed on the rosuvastatin main photoproduct (ppRSV). Indeed, the photobehavior of this dihydrophenanthrene-like compound presents the essential components needed for an efficient biomolecule photosensitizer i.e. (i) a high intersystem crossing quantum yield (Φ(ISC) = 0.8), (ii) a triplet excited state energy of ca. 67 kcal mol(-1), and (iii) a quantum yield of singlet oxygen formation (Φ(Δ)) of 0.3. Furthermore, laser flash photolysis studies revealed a triplet-triplet energy transfer from the triplet excited state of ppRSV to thymidine, leading to the formation of cyclobutane thymidine dimers, an important type of DNA lesion. Finally, tryptophan has been used as a probe to investigate the type I and/or type II character of ppRSV-mediated oxidation. In this way, both an electron transfer process giving rise to the tryptophanyl radical and a singlet oxygen mediated oxidation were observed. On the basis of the obtained results, rosuvastatin, through its major photoproduct ppRSV, should be considered as a potential sensitizer.

• Authors: Giacomo Nardi, Virginie Lhiaubet-Vallet, Paula Leandro-Garcia, Miguel Angel Miranda
• Journal: Chemical research in toxicology (Chem Res Toxicol) Vol. 24 Issue 10 Pg. 1779-85 (Oct 17 2011) ISSN: 1520-5010 [Electronic] United States
• PMID: 21923146 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Fluorobenzenes
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Phenanthrenes
• Photosensitizing Agents
• Pyrimidines
• Reactive Oxygen Species
• Sulfonamides
• Singlet Oxygen
• Rosuvastatin Calcium

Topics

• Dermatitis, Phototoxic
• Fluorobenzenes (chemistry, radiation effects)
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (chemistry, radiation effects)
• Lasers
• Phenanthrenes (chemistry)
• Photolysis
• Photosensitizing Agents (chemistry, radiation effects)
• Pyrimidines (chemistry, radiation effects)
• Reactive Oxygen Species (chemistry)
• Rosuvastatin Calcium
• Singlet Oxygen (chemistry)
• Spectrophotometry, Ultraviolet
• Sulfonamides (chemistry, radiation effects)