Photosensitization induced by the antibacterial fluoroquinolone Rufloxacin leads to mutagenesis in yeast.
Rufloxacin (RFX) is an antibacterial fluoroquinolone that exhibits UVA photosensitization properties. Photosensitization reactions lead to the formation of oxidative damage, mainly via singlet oxygen. Here we explore the phototoxic and photomutagenic potency of RFX using a panel of yeast (Saccharomyces cerevisiae) mutants affected in different DNA repair pathways. Yeast mutants provide a sensitive tool to identify the photodamage and the DNA repair pathways that cope with it. Cell viability test at increasing dose of UVA shows that both the DNA repair deficient and wild type cells are equally sensitive to RFX-induced photosensitization, demonstrating that phototoxic effect is not due to DNA injury. Photomutagenicity of RFX is evaluated by measuring the frequency of forward Can(R) mutations. The mutation induction is low in wild type cells. A high increase in mutation frequency is observed in strains affected in Ogg1 gene, compared to wild type and other base excision repair deficient strains. The mutation spectrum photomediated by RFX in wild type cells reveals a bias in favour of GC>TA transversions, whereas transition and frameshift mutations are less represented. Altogether data demonstrates that 8-oxo-7,8-dihydroguanine (8-oxoGua) is by far the major DNA damage produced by RFX photosensitization, leading to mutagenesis. We also explore the role played by DNA mismatch repair, translesion synthesis and post-replication repair in the prevention of mutagenic effects due to RFX exposure. In addition, we show that most of RFX photodegradation products are not mutagenic. This study defines the phototoxic and photomutagenic properties of antibacterial RFX and point out possible unwanted side effects in skin under sunlight.
Serrentino
Maria-Elisabetta
ME
Institut Curie, Centre de Recherche, Centre Universitaire, F-91405 Orsay, France.
Catalfo
Alfio
A
Angelin
Anne-Reynaud
AR
de Guidi
Guido
G
Sage
Evelyne
E
D000900:Anti-Bacterial Agents / Q000633:toxicity*; D004260:DNA Repair; D024841:Fluoroquinolones / Q000633:toxicity*; D006147:Guanine / Q000031:analogs & derivatives / Q000096:biosynthesis; D016296:Mutagenesis; D009153:Mutagens / Q000633:toxicity*; D010787:Photosensitivity Disorders / Q000235:genetics*; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics*; D014466:Ultraviolet Rays / Q000009:adverse effects
D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D009153:Mutagens; C024829:8-hydroxyguanine; D006147:Guanine; C060328:rufloxacin