In vitro phototoxicity of dihydropyridine derivatives: a photochemical and photobiological study.
Some photosensitizing drugs can cause phototoxic skin responses even after systemic administration; therefore, avoidance of undesired side-effects is a key consideration in drug discovery and development. As a prediction tool for phototoxic risk, we previously proposed the monitoring of reactive oxygen species (ROS) generated from compounds irradiated with UVA/B, which can be effective for understanding photochemical/photobiological properties. In this investigation, we evaluated the photosensitizing properties of a novel dihydropyridine derivative, with bradykinin B(2) receptor antagonist activity (compound A) using our ROS assay and several analytical/biochemical techniques. Exposure of compound A, and several dihydropyridine-type calcium channel antagonists to simulated sunlight resulted in the significant production of singlet oxygen, superoxide, or both, which indicates their photosensitive/phototoxic potential. This is consistent with the observation that compound A under UVA/B light exposure caused significant photodegradation and even peroxidation of fatty acid, which could lead to phototoxic dermatitis. Interestingly, the addition of radical scavengers, especially GSH, MPG and BHA, could attenuate the lipid peroxidation, suggesting the involvement of ROS generation in the phototoxic pathways of compound A. In the 3T3 neutral red uptake phototoxicity test, compound A also showed a phototoxic effect on 3T3 mouse fibroblast cells. These findings also support the usefulness of the ROS assay for the risk assessment studies on the drug-induced phototoxicity even at the early stages of pharmaceutical development.
Onoue
Satomi
S
Worldwide Pharmaceutical Sciences, Pfizer Global Research and Development (PGRD), Nagoya Laboratories, Pfizer Japan Inc., 5-2 Taketoyo, Aichi 470-2393, Japan. onoue@u-shizuokia-ken.ac.jp
Igarashi
Naoko
N
Yamauchi
Yukinori
Y
Murase
Noriaki
N
Zhou
Yu
Y
Kojima
Takashi
T
Yamada
Shizuo
S
Tsuda
Yoshiko
Y
D016475:3T3 Cells; D000818:Animals; D065094:Bradykinin B2 Receptor Antagonists; D002121:Calcium Channel Blockers / Q000528:radiation effects* / Q000633:toxicity*; D004396:Coloring Agents / Q000378:metabolism; D017484:Dermatitis, Phototoxic; D004095:Dihydropyridines / Q000528:radiation effects* / Q000633:toxicity*; D019787:Linoleic Acid / Q000494:pharmacology / Q000528:radiation effects; D015227:Lipid Peroxidation; D051379:Mice; D009499:Neutral Red / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014466:Ultraviolet Rays
D065094:Bradykinin B2 Receptor Antagonists; D002121:Calcium Channel Blockers; D004396:Coloring Agents; D004095:Dihydropyridines; D017382:Reactive Oxygen Species; D017392:Thiobarbituric Acid Reactive Substances; D009499:Neutral Red; D019787:Linoleic Acid