Melanocyte melanin augments sparfloxacin-induced phototoxicity
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.
References (25)
- et al.
Enoxacin raises plasma theophylline concentrations
Lancet
(1984) Bullous photoreaction to nalidixic acid
Am J Med
(1975)- et al.
Mechanistic studies of the phototoxic potential of PD 117596, a quinolone antibacterial compound
Toxicol Appl Pharmacol
(1991) - et al.
Sparfloxacin-induced photosensitivity and the occurrence of a lichenoid tissue reaction after prolonged exposure
J Am Acad Dermatol
(1998) - et al.
Ofloxacin in human hair determined by high performance liquid chromatography
Forensic Sci Int
(1991) - et al.
Specific toxicologic aspects of the quinolones
Rev Infect Dis
(1988) Adverse effects of the fluoroquinolones
Rev Infect Dis
(1988)Quinolone toxicity: methods of assessment
Am J Med
(1991)- et al.
Seizure discharges induced by the combination of new quinolinecarboxylic acid antimicrobial drugs and non-steroidal anti-inflammatory drugs
Chemotherapy
(1988) Possible role for the new fluoroquinolones (levofloxacin, grepafloxacin, trovafloxacin, clinafloxacin, sparfloxacin, and DU-6859a) in the treatment of anaerobic infections: review of current information on efficacy and safety
Clin Infect Dis
(1996)