Pitavastatin, a new HMG-CoA reductase inhibitor, induces phototoxicity in human keratinocytes NCTC-2544 through the formation of benzophenanthridine-like photoproducts.
This study reports the results of an investigation of the phototoxicity mechanism induced by pitavastatin and its photoproducts, namely 6-cyclopropyl-10-fluoro-7,8-dihydrobenzo[k]phenanthridine (PP3) and 6-cyclopropyl-10-fluorobenzo[k]phenanthridine (PP4). The phototoxicity was tested in human keratinocytes cell lines NCTC-2544, and the results proved that under the same conditions, all three compounds exhibited phototoxic effects in the model tested. The reduction in cell viability was found to be both concentration- and UVA dose-dependent. A point of note is that both the photoproducts produced a dramatic decrease in cell viability with GI(50) values one order of magnitude lower compared to the parent compound. In particular, the fully aromatic derivative (PP4) showed the highest antiproliferative activity. Flow cytometric analysis indicated that pitavastatin and the photoproduct PP4 principally induced necrosis, as revealed by the large appearance of propidium iodide-positive cells and also confirmed by the rapid drop in cellular ATP levels. Further studies committed to better understanding of photoinduced cell death mechanism(s) revealed that neither pitavastatin nor PP4 induced mitochondrial depolarization or lysosomal damage, but, interestingly, extensive cell lipid membrane peroxidation along with a significant oxidation of model proteins occurred, suggesting that pitavastatin and PP4 exert their phototoxic effect mainly in the cellular membranes. The present results suggest that the phototoxicity of pitavastatin may be mediated by the formation of benzophenanthridine-like photoproducts that appear to have high potential as photosensitizers.
Department of Pediatrics, Laboratory of Oncohematology, University of Padova, Via Giustiniani 3, 35128 Padova, Italy. giampietro.viola.1@unipd.it
Giampietro
G
Viola
Pawel
P
Grobelny
Maria Antonella
MA
Linardi
Alessia
A
Salvador
Stefano
S
Dall'Acqua
Łukasz
Ł
Sobotta
Jadwiga
J
Mielcarek
Francesco
F
Dall'Acqua
Daniela
D
Vedaldi
Giuseppe
G
Basso
D000255:Adenosine Triphosphate / Q000378:metabolism; D053119:Benzophenanthridines / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D017484:Dermatitis, Phototoxic / Q000209:etiology*; D005609:Free Radicals; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000633:toxicity*; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D010782:Photolysis; D017319:Photosensitizing Agents / Q000633:toxicity; D011804:Quinolines / Q000737:chemistry / Q000633:toxicity*; D014466:Ultraviolet Rays
D053119:Benzophenanthridines; D005609:Free Radicals; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017319:Photosensitizing Agents; D011804:Quinolines; D000255:Adenosine Triphosphate; C108475:pitavastatin