title: Photomutagenicity of anhydroretinol and 5,6-epoxyretinyl palmitate in mouse lymphoma cells.
abstract: Retinyl palmitate (RP) is frequently used as an ingredient in cosmetics and other retail products. We previously reported that, under UVA light irradiation, RP is facilely decomposed into multiple products, including anhydroretinol (AR) and 5,6-epoxyretinyl palmitate (5,6-epoxy-RP). We also determined that combined treatment of mouse lymphoma cells with RP and UVA irradiation produced a photomutagenic effect. In this study, we evaluated the photomutagenicity of AR and 5,6-epoxy-RP, in L5178Y/Tk+/- mouse lymphoma cells. Treatment of cells with AR or 5,6-epoxy-RP alone at 10 and 25 microg/mL for 4 h did not show a positive mutagenic response. However, because these doses did not induce the required amount of cytotoxicity for mouse lymphoma assay, we are unable to determine whether or not these two compounds are mutagenic. Treatment of cells with 1-25 microg/mL AR or 5,6-epoxy-RP under UVA light (315-400 nm) for 30 min (1.38 mW/cm2) produced a synergistic photomutagenic effect. At 10 microg/mL (37.3 microM) AR with UVA exposure, the mutant frequency (MF) was about 3-fold higher than that for UVA exposure alone, whereas the MF for 25microg/mL (46.3microM) of 5,6-epoxy-RP + UVA was approximately 2-fold higher than that for UVA exposure alone. Compared with previous results for RP + UVA treatment, the potency of the induced phototoxicity and photomutagenicity was AR > RP > 5,6-epoxy-RP. To elucidate the underlying photomutagenic mechanism, we examined the loss of heterozygosity (LOH) at four microsatellite loci spanning the entire chromosome 11 for mutants induced by AR or 5,6-epoxy-RP. Most mutants lost the Tk+ allele, and more than 70% of the chromosome damage extended to 38 cM in chromosome length. AR + UVA induced about twice as many mutants that lost all four microsatellite markers from the chromosome 11 carrying the Tk+ allele as RP + UVA or 5,6-epoxy-RP + UVA. These results suggest that two of RP's photodecomposition products are photomutagenic in mouse lymphoma cells, causing events that affect a large segment of the chromosome.
authors.affiliation: Division of Genetic, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas 72079, USA. nan.mei@fda.hhs.gov
authors.forename: Nan
authors.initials: N
authors.lastname: Mei
authors.forename: Qingsu
authors.initials: Q
authors.lastname: Xia
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
authors.forename: Martha M
authors.initials: MM
authors.lastname: Moore
authors.forename: Tao
authors.initials: T
authors.lastname: Chen
authors.forename: Peter P
authors.initials: PP
authors.lastname: Fu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019656:Loss of Heterozygosity; D008223:Lymphoma / Q000188:drug therapy* / Q000235:genetics*; D051379:Mice; D015394:Molecular Structure; D009152:Mutagenicity Tests; D009153:Mutagens / Q000737:chemistry / Q000633:toxicity*; D010168:Palmitates / Q000633:toxicity*; D010777:Photochemistry; D015398:Signal Transduction; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000633:toxicity; D014466:Ultraviolet Rays; D014801:Vitamin A / Q000031:analogs & derivatives* / Q000633:toxicity
chemical_list: C520252:5,6-epoxyretinyl palmitate; D009153:Mutagens; D010168:Palmitates; D014801:Vitamin A; C031469:anhydrovitamin A; D014212:Tretinoin