Upstream eventOxidation of membrane lipids
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Reactive oxygen species generated from photoreactive chemicals leading to phototoxic reactions||adjacent||High||Low|
Life Stage Applicability
|All life stages||High|
Key Event Relationship Description
Oxidation of membrane lipids can lead to inflammatory events via oxidative damage of cellular membranes and increases in expression of pro-inflammatory cytokines.
Evidence Supporting this KER
Lipid peroxidation in cellar membrane is an oxidative damage of cellular membrane, and viability of cells decreases by lipid peroxidation of photoreactive chemicals (Castell et al., 1994).
Increases in lipid peroxidation and inflammatory-related cytokines were observed in the murine skin, and naringenin, an anti-oxidant, attenuated these increases in a dose-dependent manner (Martinez et al., 2015).
Benzoyl peroxide, a ROS generator, led to lipid peroxidation and GSH depletion, and the changes caused the gene expression of pro-inflammatory cytokines in human keratinocytes (Valacchi et al., 2001).
Uncertainties and Inconsistencies
Quantitative Understanding of the Linkage
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Chemicals: This KER applies to a wide range of chemicals. The chemicals generate ROS under exposure to light (290-700 nm) (ICH, 2014, Onoue and Tsuda, 2006).
Sex: This KER applies to both males and females.
Life stages: The relevant life stages for this KER are all life stages after born.
Taxonomic: This KER mainly applies to human.
Castell JV, Gomez-Lechon MJ, Grassa C, Martinez LA, Miranda MA, Tarrega P. Photodynamic lipid peroxidation by the photosensitizing nonsteroidal antiinflammatory drugs suprofen and tiaprofenic acid. Photochem Photobiol. 1994;59:35-9.
ICH. ICH Guideline S10 Guidance on Photosafety Evaluation of Pharmaceuticals.: International Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use; 2014.
Martinez RM, Pinho-Ribeiro FA, Steffen VS, Caviglione CV, Vignoli JA, Barbosa DS, et al. Naringenin Inhibits UVB Irradiation-Induced Inflammation and Oxidative Stress in the Skin of Hairless Mice. Journal of natural products. 2015;78:1647-55.
Onoue S, Tsuda Y. Analytical studies on the prediction of photosensitive/phototoxic potential of pharmaceutical substances. Pharmaceutical research. 2006;23:156-64.
Valacchi G, Rimbach G, Saliou C, Weber SU, Packer L. Effect of benzoyl peroxide on antioxidant status, NF-kappaB activity and interleukin-1alpha gene expression in human keratinocytes. Toxicology. 2001;165:225-34.