Review articleQuinolone photoallergy: Photosensitivity dermatitis induced by systemic administration of photohaptenic drugs
Introduction
Quinolone derivatives are widely used as oral antibacterial drugs. Fluoroquinolones, also known as `new quinolones', are the currently well-prescribed quinolones with fluorine at the 6 position of the structural backbone. They exert a bacteriocidal effect by inhibiting DNA gyrase with a broad spectrum of therapeutic activity that includes Gram-positive and Gram-negative bacteria, anaerobes, and even mycobacteria [1]. Representative fluoroquinolones include lomefloxacin (LFLX), ciprofloxacin (CPFX), norfloxacin (NFLX), ofloxacin (OFLX), levofloxacin (LVLX, s-isomer of OFLX), enoxacin (ENX), sparfloxacin (SPFX), fleroxacin (FLRX), and tosufloxacin (TFLX) (Fig. 1).
Drugs are one of the important causative agents of photosensitivity manifesting as skin responses upon exposure to sunlight [2]. There have been reported 373 Japanese cases of drug-induced photosensitivity from 1980 to 1996, and 142 (38%) are caused by fluoroquinolones [3]. Thus, photosensitivity is one of the major adverse effects of fluoroquinolones. Like other photosensitive drugs, both phototoxicity 1, 4, 5, 6, 7, 8, 9, 10and photoallergy 9, 11, 12, 13, 14, 15play a role in the pathogenesis of fluoroquinolone photosensitivity. The incidence of occurrence of photosensitivity varies among fluoroquinolones (Table 1). The majority of patients developed photosensitive dermatitis to either of ENX, LFLX, SPFX, or FLRX. The highest incidence of SPFX can be explained with its outstanding phototoxicity [5]. Photosensitivity to ENX and FLRX seems to be mainly photoallergic based on clinical studies 11, 16, 17, while LFLX is thought to have both potencies 12, 13, 14, 15. Ultraviolet A light (UVA) is the main action spectrum in fluoroquinolone photoallergy 11, 12, 13. On the other hand, there is potential synergism between UVA and UVB in their phototoxic reactions, as photosensitivity dermatitis to SPFX is evoked by photoaugmentation between UVA and UVB [5].
In contrast to many in vivo and in vitro studies on fluoroquinolone phototoxicity, their photoallergenicity has only recently begun to be intensively investigated. This review will focus on the photochemical and immunological mechanisms of quinolone photoallergy mainly based on our findings from both the mouse model of and patients with fluoroquinolone photosensitivity.
Section snippets
Covalent photocoupling of fluoroquinolones to protein and cells: a photohaptenic property
A photohaptenic moiety is one of the salient properties of allergically photosensitizing chemicals as has been well demonstrated with 3,3′,4′,5-tetrachlorosalicylanilide (TCSA). TCSA induces and elicits allergic contact photosensitivity when topically applied to skin and subsequently irradiated with UVA 18, 19. Upon exposure to UVA, protein is covalently coupled [20]and cells are easily conjugated 21, 22with this low molecular weight chemical. TCSA-conjugation of cutaneous epidermal cells
Presence of quinolone-photoadducts in fluoroquinolone-photomodified epidermal cells as detected by monoclonal antibody (mAb) ST-Q-9
We attempted to generate monoclonal antibody directed against fluoroquinolone-photoadducts by immunizing mice with CPFX-photomodified, syngeneic spleen cells. After fusion of spleen cells from an immunized mouse with myeloma cells, we raised an mAb, ST-Q-9 (IgM, κ), which reacted with cells photomodified with any of nine fluoroquinolones shown in Fig. 1. Therefore, this mAb recognizes the common part of structure in fluoroquinolones. Quinolone photoadducts were detected in in vitro
Induction and elicitation of cutaneous photoallergic sensitivity to fluoroquinolones with quinolone-photomodified epidermal cells
Fluoroquinolone photoallergy is inducible in mice, when they are sensitized with systemic administration of fluoroquinolone and following UVA irradiation of shaved abdomen and challenged with systemic quinolone and UVA exposure of earlobes 15, 31. This is closely related to human photoallergy in terms of the manner of administration of photoallergen and of irradiation of skin with UVA. Alternatively, we can sensitize and elicit animals by a subcutaneous injection of
Induction of T cell responses with fluoroquinolone-photomodified Langerhans cells (LC)
Sensitized T cells are present in lymph nodes from mice immunized subcutaneously with fluoroquinolone-photomodified epidermal cells [31]. In patients administered with fluoroquinolone and exposed to UVA, LC are one of the candidates to serve as antigen-presenting cells in the initiation of fluoroquinolone photoallergy, as evidenced in TCSA contact photoallergy [32]. LC-enriched epidermal cells, containing 10–15% LC, effectively induced the proliferation of immune lymph node T cells when
Cross-reactivity among fluoroquinolones in T cell and immunoglobulin (Ig) recognition
There have been several clinical reports concerning cross-reactivity between fluoroquinolones. Patients with LFLX photosensitivity have been reported to show positive photopatch testing for ENX [13]and CPFX [14]as well as LFLX. Besides photosensitivity, cross-reactivity was also found between CPFX and NFLX in patients with fixed drug eruption [38]. When mice sensitized with LFLX- or OFLX-photomodified epidermal cells were challenged with LFLX-, CPFX-, NFLX-, OFLX-, ENX-, or SPFX-photomodified
Murine fluoroquinolone photoallergy is mediated by T cell receptor Vβ13-positive Th1 cells
When immune lymph node cells of fluoroquinolone-sensitized mice were cultured with the corresponding quinolone-photomodified cells in the presence of interleukin (IL)-2, T cells expressing T cell receptor Vβ13 preferentially propagated in response to photoantigen. T cell lines thus established from LFLX-, CPFX-, or NFLX-immune lymph node cells commonly bore CD4 and T cell receptor Vβ13 [31]. Furthermore, Vβ13+ cells also exclusively expanded, when LFLX-immune lymph node cells were cultured in
Photobinding potency and phototoxicity of fluoroquinolones influence their photoallergenicity
Although all fluoroquinolones examined are photoantigenically active and cross-reactable, there are differences in the degree of photoallergenicity. As assessed by the response of immune lymph node cells to quinolone-photomodified LC, the in vivo immunizing potencies of six fluoroquinolones decrease in the order: LFLX, CPFX, NFLX>OFLX, ENX>SPFX [31]. However, when evaluated by the in vitro ability of photomodified LC to stimulate immune lymph node cells, the in vitro challenging potencies
Photochemistry and protein-binding and antigenic sites of fluoroquinolones
There are several apparent relationships between the chemical structure of quinolones and photosensitivity [1]. The phototoxicity is determined at least partly by the nature of substituents at the 8-position of the structure [41], as exemplified by SPFX and LFLX though the former's activity is higher than the latter's [5]. This fluorine is not involved in the photoallergenicity, because CPFX and NFLX, possessing no fluorine at C8, show stronger photoallergenicity than SPFX. The fluorine at C6,
Conclusion
Taken together a cascade of quinolone photosensitivity, the initial event is photoconjugation of epidermal cells with quinolones by UVA irradiation in the skin of patients medicated with quinolones. The formed quinolone-photocoupled LC may induce immunologic reactions mediated by T cells that recognize the shared structure of quinolones. However, since there are differences between fluoroquinolones in the photobinding and phototoxic potencies, their photoallergic abilities are substantially
Acknowledgements
I acknowledge that a part of studies in this review were performed in collaboration with Drs Naohiro Seo, Hiroaki Yagi, and Akihiro Ohshima. I am grateful to Professor Masahiro Takigawa for his support. This work was supported in part by a grant from the Ministry of Education, Science, Sports and Culture of Japan.
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