Melanocyte melanin augments sparfloxacin-induced phototoxicity

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Abstract

Quinolone has become one of the common causative agents of drug-induced photosensitive dermatitis, and its phototoxicity has now become a clinical issue. The mechanisms of long-lasting phototoxicity induced by sparfloxacin (SPFX) were investigated using melanotic and amelanotic melanoma cell lines. The sensitivities to SPFX and UVA irradiation up to 6 J/cm2 of both cells were not significantly different. However, the melanotic melanoma cell cultured with 1–150 μg/ml of SPFX showed significantly higher sensitivity to UVA irradiation compared with that of the amelanotic melanoma cell. By pulse culture with SPFX, the bound SPFX level of melanotic cell line was 10–20 times higher than that of the amelanotic cell line. These data strongly suggest that the melanin in melanocytes and keratinocytes accumulates the antibacterial quinolone and increases its tissue concentration in the basal epidermis and contributes to the long-lasting photo-injury and liquefaction degeneration of the basal cells in antibiotic quinolone phototoxic dermatitis.

Introduction

Fluoroquinolone antibacterial agents are widely used as oral preparations. They have been under development worldwide since the discovery of nalidixic acid in the 1960s. Great progress has been made in broadening their antibacterial spectrum against both gram-positive and -negative bacteria, as well as in improving their pharmacokinetic profiles. However, they occasionally showed specific side-effects, e.g. gastrointestinal and central nervous system symptoms [1], [2], juvenile joint toxicity [3], convulsion induction under conditions of concomitant mediation with nonsteroidal anti-inflammatory drugs and theophylline [4], [5], or dermatological side effects. The dermatological side effects of new quinolones are polymorphic; phototoxicity [2], [6], photoallergy [7], vasculitis [8] and subcorneal pustular eruptions [9] have been reported. Among them, phototoxicity reaction has been well documented in quinolones. In the early 1970s, many cases of phototoxicity caused by nalidixic acid were reported in clinical practice [3], [10], [11], and there have been many case-reports, safety profile studies and clinical trial records of phototoxicity caused by other newer quinolones [2], [6], [12], [13]. In the mechanism of quinolone phototoxicity, many reports have demonstrated that the reactive oxygens derived from the quinolones, i.e. hydroxyl radicals and/or singlet oxygen during UVA irradiation, may attack and damage biological membranes, so that the inflammatory reaction is then augmented by secondary generated toxic oxidants [14], [15], [16].

Among the quinolones, sparfloxacin (SPFX) has strong antibacterial effects based on its an extra-long half time and high tissue distribution [17], [18]. However, shortly after the introduction of SPFX, many severe cases of phototoxic dermatitis were reported in Japan [19], [20], [21]. In particular, SPFX-induced phototoxic dermatitis occasionally persists after the cessation of administration.

In addition, SPFX-induced phototoxic dermatitis shows characteristic histological changes with basal cell liquefaction and later lichenoid tissue reactions [21]. These findings implicate the involvement of a mechanism for basal layer tropic injury. On the other hand, although quinolones including SPFX bind well to melanin-rich tissue such as hair and eyes [22], the relation between the affinity to melanin of quinolones and phototoxicity is not well documented. If cutaneous melanin accumulates quinolone, the melanin would enhance rather than protect against phototoxicity.

In this study, we investigated the melanin-dependent accumulation of SPFX and its influence on UV-induced cell toxicity.

Section snippets

Cells and cell culture

Two human melanoma cell lines were used. The melanoma cell line MM418 (MM) produces melanin abundantly. The amelanotic melanoma cell line MM96E (AM) has a high tyrosinase activity but does not produce melanin. Both cell lines were the gift of Dr Peter G. Parsons (Queensland Institute of Medical Research, Herston, Australia). The cells were cultured in RPMI1640 medium (Handai Biken, Osaka, Japan) containing 5% heat-inactivated fetal calf serum (FCS) (Biocell, Carson, CA), penicillin (100 IU/ml),

Phototoxicity of SPFX

The viability of the MM and AM cells decreased dependent on the concentration of SPFX (1–150 μg/ml) in the culture media without exposure to UVA. SPFX was toxic at a concentration of 400 μg/ml on both cell lines. There was no significant difference between the viability of the two cell lines at each concentration of SPFX (Fig. 1).

Both the MM and AM cells were resistant to UVA irradiation without SPFX. UVA irradiation at 1 J/cm2 slightly decreased the viability of both cell lines. However, no

Discussion

In light of the increased clinical use of the anti-bacterial quinolones, the phototoxicity of quinolones has become a clinical issue. In general, the clinical effectiveness of antibiotics increases dependent on their tissue concentrations and biological half-lives, factors which also contribute to the occurrence of side effects. A clinical study of SPFX-photosensitive dermatitis indicated SPFX dose-dependency and sun exposure duration-dependency [19], [21]. Therefore, a photoallergic mechanism

Acknowledgements

This work was supported in part by a research grant from the Ministry of Education, Science and Culture of Japan.

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