An evaluation of chemical photoreactivity and the relationship to photogenotoxicity.
In the accompanying paper (Kleinman et al., submitted for publication), the link between phototoxicity and photoreactivity (i.e. production of singlet oxygen, superoxide and chemical photostability) has been established. It is proposed this may be used to refine existing triggers for photosafety testing. Using a series of compounds we have determined whether these photochemical reactivity measurements may be used to mechanistically predict phototoxic and/or photogenotoxic liability. Therefore, a subset of compounds tested in the in vitro 3T3 NRU assay from the accompanying paper were tested in the photo-chromosome aberration assay in CHO cells, using standard methodologies. The results of these studies indicate that photochemical analysis of compounds is a good predictor of in vitro phototoxicity, but not necessarily, photoclastogenicity. Further evidence from photostability experiments suggests that this is due to the differences in UVR irradiance and exposure conditions between the two assays. Nevertheless, this approach may provide a more robust trigger for the need to conduct in vitro and/or in vivo photosafety studies than simple UV/visible absorbance spectra.
Lynch
Anthony M
AM
GlaxoSmithKline, Ware, Hertfordshire, UK. Anthony.M.Lynch@GSK.com
Smith
Mark D
MD
Lane
Amy S
AS
Robinson
Sharon A
SA
Kleinman
Mark H
MH
Kennedy-Gabb
Sonya
S
Wilcox
Philip
P
Rees
Robert W
RW
D016475:3T3 Cells; D000818:Animals; D016466:CHO Cells; D002869:Chromosome Aberrations; D006224:Cricetinae; D003412:Cricetulus; D017484:Dermatitis, Phototoxic / Q000209:etiology*; D004355:Drug Stability; D064420:Drug-Related Side Effects and Adverse Reactions; D051379:Mice; D009152:Mutagenicity Tests / Q000379:methods; D004364:Pharmaceutical Preparations / Q000737:chemistry; D055668:Photochemical Processes; D010777:Photochemistry / Q000379:methods*; D010782:Photolysis; D026082:Singlet Oxygen / Q000737:chemistry; D013481:Superoxides / Q000737:chemistry; D014466:Ultraviolet Rays
D004364:Pharmaceutical Preparations; D013481:Superoxides; D026082:Singlet Oxygen