Binding of drugs to eye melanin is not predictive of ocular toxicity

Binding of Drugs to Eye Melanin Is Not Predictive of Ocular Toxicity B. Leblanc,* S. Jezequel,† T. Davies,‡ G. Hanton,* and C. Taradach* *Pfizer, Central Research, BP 159, 37401 Amboise, France; Pfizer, Central Research, Ramsgate Road, Sandwich, Kent CT13 9NJ, England; and Pfizer, Central Research, Eastern Point Road, Groton, Connecticut 06340 cussed. The purpose of this review is to help dispel Ocular melanin is found in the uveal tract and in the
concerns about the binding of radiolabeled molecules to pigmented epithelial layer of the retina. Many struc-
the eye of pigmented rats in autoradiographic studies.
turally and pharmacologically unrelated drugs from
The review also addresses the issue of whether toxicity different therapeutic classes bind to melanin. Exam-
studies are best conducted in albino or pigmented an- ples include numerous drugs acting on the central
nervous system, -blockers, -agonists, antimalarial
drugs, sympathomimetic amines, and antibiotics. The

critical factors are the acid/base status and the li-
pophilicity of the molecule. In all cases, there are no

The wall of the eyeball which encloses the anterior direct consequences of drug–melanin binding. Drug-
and posterior chambers, the lens, and the vitreous related toxic effects on the retina described in humans
humor consists of three layers (Bloom and Fawcett, and animals are unrelated to melanin binding: mela-
1975). The outer fibrous layer is divided into the trans- nin binding and retinal toxicity are two separate en-
parent clear cornea and the opaque white sclera. A tities, the latter being related to the intrinsic toxicity
middle vascular layer also known as the uveal tract is of the compound rather than its ability to bind. Chlo-
composed of the iris anteriorly, an intermediate ciliary roquine and phenothiazines are often used as exam-
body, and the choroid posteriorly. The choroid which ples of drugs with retinal toxicity linked to melanin
supports and nourishes the retina consists of thin, binding. In both cases however, experimental data
loose, highly vascularized, connective tissue which con- show that the toxic mechanism is unrelated to bind-
tains many pigmented melanocytes. Some species such ing. Melanin binding has also been found to be protec-
as dog, cat, and ferret have a specialized layer in the tive against the ocular toxicity of some drugs. In con-
choroid, the tapetum lucidum. Bright reflection from clusion, we believe that potential ocular toxicity of
future drugs can be assessed adequately by conduct-

the tapetum causes the so-called “eye shine” (Rubin, ing well-designed toxicology studies, and using non-
pigmented rodents in addition to pigmented nonro-
The innermost layer of the wall of the eyeball, the dent species remains fully justified. Binding of drugs
retina, covers the inner surface of the choroid. The to eye melanin is not predictive of ocular toxicity.
retina is composed of multiple layers which can be 1998 Academic Press
distinguished in routine histological tissue sections.
The outermost layer of the retina, the retinal pig-mented epithelium (RPE) or pars pigmentosa, is com- INTRODUCTION
posed of a monolayer of polygonal cells which is con-tinuous cranially with the pigmented epithelial layer of Since the early reports on chloroquine and the phe- the ciliary body and the epithelium of the iris. The RPE nothiazines (see below), there has been frequent spec- cells of pigmented animals contain melanin in melano- ulation on the possible relationship between oculotox- somes or melanin granules. In species with a tapetum, icity and binding of drugs to melanin. The concern is the RPE overlying it is not pigmented. The RPE has based upon the potential accumulation and persistence three main functions: phagocytosis and degradation of of drug in melanin-containing tissues of the eye. This the continuously shedding tips of photoreceptor cells, phenomenon raises the possibility of oculotoxicity fol- vitamin A transport and storage, and active ion trans- port. The RPE together with the capillary wall consti- This review will be limited to the putative ocular effects of melanin binding. Available literature is re- The remaining retinal layers comprise the neuro- viewed and the relevance of melanin binding to the retina or pars nervosa. It is a highly differentiated safety assessment of pharmaceutical compounds is dis- structure with many different types of neurons which Copyright 1998 by Academic PressAll rights of reproduction in any form reserved.
DRUG MELANIN BINDING IS NOT OCULAR TOXICITY are very specifically connected to each other. The neu- structure of melanins remains elusive (Raghavan et roretina contains photoreceptor cells (rods and cones al., 1990). Melanin consists of highly heterogeneous which capture and transduce light to chemical signals polymers of various units that include 5,6-dihydroxy- and are in contact with the RPE), cells that respond indole-2-carboxylic acid and pyrole-carboxylic acid (Ito, with a slow change in membrane potential (bipolar 1986). Melanins are therefore polyanions with a rela- cells, horizontal cells, amacrine cells), neurons that tively high content of carboxyl groups and semiquino- produce action potentials (ganglion cells), and glial nes. NMR studies with various enantiomers of ephed- cells (Muller cells, oligodendrocytes).
rine have also indicated that there is potential forsteric preference of binding (Salazar-Bookaman et al., BIOLOGY OF MELANIN
The precise nature of the binding of drugs to melanin Melanins are a ubiquitous class of biological pig- has not been fully elucidated. Although in principle ments (Kollias et al., 1991). There are basically two drugs may bind either reversibly or irreversibly to oc- types of melanin in the animal kingdom: eumelanin, ular melanin (Rubin and Weisse, 1992), there is evi- which is brown or black, and phaeomelanin, which is dence to suggest that the association of most drugs red or yellow. Most visible pigmentation in mammals with melanin is a reversible process: the turnover of results from the synthesis and distribution of the two melanin is low, whereas most drugs which bind are types of melanin, whereas feather coloration in birds is due to carotenoid pigments (Hearing and Tsukamato, static forces play an important role in the binding in 1993). The pigmentation is genetically controlled at most cases, including chloroquine and chlorpromazine multiple levels, including migration of melanocytes (Tjalve et al., 1981). In addition, van der Waals forces during embryogenesis and melanin synthesis at cellu- or charge transfer may contribute to the binding of lar, subcellular, and enzymatic levels. More than 150 such drugs. There is little or no evidence for covalent mutations affecting pigmentation in mice have been binding of drugs to melanin. Mason (1977) suggests identified at more than 50 different genetic loci (Hear- that the tighter binding encountered with some drugs may be the result of such interactions.
Melanin synthesis involves the enzymatic conver- The ubiquity with which compounds distribute to the sion of the amino acid tyrosine via intermediates in- eye is well illustrated by a study in which the distri- cluding dihydroxyphenylalanine (dopa) to melanin bution of 27 compounds to the melanin-containing (Wheater et al., 1979). Detailed molecular studies of structures of the eye was shown to correlate well with melanin synthesis have shown that it is a very complex their physicochemical properties (Zane et al., 1990). A process involving multiple enzymes (Hearing and drug’s affinity for melanin is reported to be directly Tsukamato, 1993). Of all enzymes involved in the pro- related to acid/base status and lipophilicity of the mol- cess, only tyrosinase is essential for the production of ecule. We have corroborated these findings by review- both varieties of melanin. Most types of albinism, de- ing the literature for drugs reported to bind to melanin, fined as the hereditary inability to synthesize melanin apparently without associated ocular effects. This com- in man and animals, are due to molecular lesions of the pilation of about 40 compounds is shown in Table 1.
Also included are physicochemical properties for these Melanin in the RPE and in other pigmented eye drugs, obtained or calculated from the Medchem data- structures shows very little turnover (Ings, 1984; base (see van de Waterbeemd, 1997). Essentially, all Sarna, 1992). Ocular pigmentation is believed to be drugs identified as binding to melanin display some formed for life in a brief period during the fetal and basicity with most pK values above 7. Similarly, most perinatal period. In the eye, pigmented cells are non- of these drugs display lipophilic characteristics as evi- dividing and practically no melanin renewal is known denced by their positive log P (octanol/water partition coefficient). These data provide solid support for the Melanin is found in higher concentrations in the eye concept that all basic/lipophilic drugs can reasonably than anywhere else in the human body (Potts, 1996).
be expected to bind to melanin. Since many drugs are Ocular melanin, particularly in the uveal tract, ab- basic and lipophilic, probably over 40% (van de Water- sorbs most of the visible light that penetrates the lens beemd, 1997), we suggest that reversible binding to and protects the retina from overexposure by prevent- melanin is a very widespread phenomenon.
ing light scatter within the eye (Ings, 1984; Sarna, The many possible consequences of interaction of 1992). Melanin in the eye may also play a protective xenobiotics with pigmented ocular tissue were re- role against free radicals (Koneru et al., 1986).
viewed by Mason (1977), Catanese et al. (1978), Ings(1984), Rubin and Weisse (1992), and Larsson (1993).
If melanin binding occurs, pigmented tissues would Melanin is a purely descriptive term which conveys attract and retain the drug. It is reasonable to expect no chemical information (Zane et al., 1990). The exact that binding to melanin of an essentially nontoxic mol- Drugs Reported to Bind to Melanin without Reported Ocular Effects
Note. (c), calculated values. pK and log P data from MedChem database (van de Waterbeemd, 1997).
a Determined in our laboratories.
ecule does not lead to toxicity (Larsson, 1993). In such binding potentially harmful substances, thus prevent- cases the tissue simply acts as a depository for the ing the development of ocular toxicity.
compound without any discernible toxicity (see nextsection). Theoretical possible adverse consequences in- MELANIN BINDING WITHOUT OCULAR EFFECTS
clude the following: (1) high concentration of drugcould produce damage to tissues accumulating the mol- There are numerous literature reports of compounds ecule; (2) binding of drug to melanin would alter its role which bind to melanin without giving rise to ocular of free radical sink, thereby triggering a deleterious effects (Ings, 1984; Salazar-Bookaman et al., 1994).
effect (Koneru et al., 1986); and (3) slow release of the Such compounds are structurally and pharmacologi- drug from melanin would prolong the exposure of tis- cally unrelated, but have similar physicochemical sues to potentially adverse (or beneficial) effects (Ma- properties (see Table 1). Drugs that bind to melanin son, 1977). Since the toxic effects of a drug are tissue or characteristically are basic and lipophilic. Undoubt- organ specific and are related to the intrinsic toxicity of edly, there are many more compounds which, based on the substance, it is clear that the presence per se of a their physicochemical properties, could be added to the xenobiotic in a tissue does not necessarily imply an list. However, published data for these compounds are adverse effect. Conversely, it is also possible that the not readily available; melanin binding properties of presence of melanin could protect susceptible cells by many drugs have not been adequately evaluated or DRUG MELANIN BINDING IS NOT OCULAR TOXICITY reported. In this respect it is of interest to note that scription of these deposits as pigments by some authors melanin binding is only exceptionally described in The is an additional confusing factor in the literature.
Physicians’ Desk Reference (PDR, 1998), which sug- Chloroquine developed as an antimalarial agent also gests that melanin binding is not viewed as key infor- has anti-inflammatory effects at much higher doses (Potts, 1996). Chronic high-dose anti-inflammatorytherapy produces a dose-dependent retinopathy. The DRUG-INDUCED RETINAL EFFECTS UNRELATED TO
first cases of chloroquine-induced retinopathy were re- MELANIN BINDING
ported in 1959 (Hobbs et al., 1959). In the early stages,patients present with bilateral visual field defects and The medical and experimental literature contains a normal maculae. In late retinopathy, the classical ap- very large volume of data regarding the putative reti- pearance is granular pigmentation of the macula sur- nal toxicology of drugs (Crews, 1968; Grant, 1974; Lar- rounded by a clear zone, surrounded by another ring of ricart, 1985; Fraunfelder, 1989; Chiou, 1992; Dukes, pigmentation, the so-called bull’s-eye macula (Dollery, 1996). Melanin binding is not implicated in drug-re- 1991). Initially, the chloroquine-induced retinopathy lated retinopathies or retinal toxicities in humans or was believed to be related to high and sustained drug laboratory animals (Frame and Carlton, 1991; Lee and concentrations in the pigmented eye as a consequence Valentine, 1990) (see Table 2). Compounds inducing of melanin binding (Bernstein et al., 1963; Potts, 1964).
adverse effects on the retina have a wide range of A keratopathy unrelated to the retinopathy can also pharmacological activities. It is noteworthy that the be observed at high doses. The keratopathy consists of substances listed in Table 2 are not associated with deposits in the cornea, presumably of chloroquine or any particular set of physicochemical properties (un- metabolite products (Potts, 1996), which could be re- like Table 1). These drugs appear to represent a fair lated to lipid complex accumulation induced by the cross-section of “all drugs” with regard to their physi- cochemical properties and provide further circumstan- Chloroquine-induced retinopathy has been studied tial evidence that melanin binding is not a causal fac- in many animal species including rat, rabbit, mouse, tor to retinal effects. Mechanisms of retinal toxicities, suspected or documented by clinical or experimental tantly, it has been reproduced both in albino and in data, include lipid complex accumulation, effects on pigmented rabbits, rats, and cats (Franc¸ois and Maud- blood vessels, enzyme inhibition, free radical genera- gal, 1964; Gregory et al., 1970; Legros and Rosner, tion, and ion disturbances (Chiou, 1992; Frame and 1971a; Kuhn et al., 1981; Ivanina et al., 1983). The severity and development of the lesion were similar in In addition, there are published reports of com- pigmented and nonpigmented animals. Furthermore, pounds which bind to melanin, but have the potential in cats photoreceptor cells were damaged in the region to cause ocular toxicity unrelated to drug–melanin of RPE without melanin covering the tapetum lucidum binding. For example, practolol binds to melanin, but and remained intact elsewhere (Kuhn et al., 1981; Iva- the ocular toxicity described with this drug is second- nina et al., 1983). The available data show that chlo- ary to a deficient tear production due to an effect on roquine induces lipid complex accumulation in the ret- lacrymal glands (Rahi et al., 1976). Topically applied ina which is characterized by the presence of many adrenaline (epinephrine) has been associated with enlarged lipid complex-containing lysosomes in the cy- macular edema in aphakic eyes (Kolker and Becker, toplasm of affected cells. Only ganglion cells, Muller 1968). Although adrenaline is known to bind to mela- cells, and bipolar cells are affected initially; no abnor- nin (Potts, 1964), the cause of the observed macular malities are seen in the RPE (Gregory et al., 1970).
edema is unknown. It is believed that the absence of a Dense cytoplasmic lamellated material has been de- lens in aphakic eyes allows topically applied adrena- tected in the retinal ganglion cells as early as after 24 h line to reach the retina by diffusion (Grant, 1974; Ob- or 3 days of treatment (Gregory et al., 1970; Lu Rauch, 1991b). In later stages, degeneration, necrosis,and cell loss affect all retinal layers including photore- CHLOROQUINE AND PHENOTHIAZINES
ceptor cells. The RPE shows a thickening and an in-crease in dense cytoplasmic material (Gregory et al., Chloroquine and phenothiazines are often used as 1970; Ivanina et al., 1983). The chronic lesions pro- examples of drugs associated with retinal toxicity duced experimentally in animals, correspond to the linked to melanin binding. Careful review of the liter- histologic description of the chloroquine-induced reti- ature shows, however, that a causal relationship be- tween the two phenomena has not been established.
It appears, therefore, that ganglion cell and photore- Furthermore, these drugs exert adverse effects on non- ceptor cell involvement is central to the development of pigmented ocular structures (cornea, lens), as a conse- chloroquine oculotoxicity, while changes in RPE cells quence of deposits of drug-related materials. The de- are secondary effects (Koneru et al., 1986). It is the Drug-Induced Retinal Effects Unrelated to Melanin Binding
Note. (c), calculated values. pK and log P data from MedChem database (van de Waterbeemd, 1997).
consequence of the affinity of chloroquine, a cationic cones (Meier-Ruge and Cerletti, 1966; Tanenbaum and amphiphilic drug, for equally amphipathic lipid bilay- ers. The drug forms complexes primarily with ganglio- Thus, it is increasingly clear that chloroquine, which is considered by many as the classical example of reti- 1991b) and thereby lead to lipid complex accumulation notoxicity due to melanin, does not exert its deleterious affecting the neuroretina (Meier-Ruge and Cerletti, effect as a result of its affinity to melanin. This is 1966; Tanenbaum and Tuffanelli, 1980). Based on further substantiated by studies which showed that what is known of other lysosomal storage diseases both flunitrazepam, a compound similar to chloro- (Summers et al., 1995), chloroquine-induced lipid com- quine, and the antimalarial agent dabequine accumu- plex accumulation has the potential to ultimately late within pigmented ocular tissues but produce no cause irreversible damage to rods and cones, although ocular toxicity (Kuhn et al., 1981; Ivanina et al., 1983).
the pathogenic mechanism has not been established Phenothiazines have been extensively used as anti- ¨ llman-Rauch, 1991b). It has been suggested that psychotic drugs since their introduction in 1953. On since at high concentrations chloroquine binds signifi- the basis of structure–activity relationships, phe- cantly to DNA, it may ultimately interfere with protein nothiazines have been classified into three groups synthesis leading to secondary destruction of rods and (groups I, II, and III). Ocular complications following DRUG MELANIN BINDING IS NOT OCULAR TOXICITY long-term, high-dose, phenothiazine therapy may in- Weisse (1992). Vigabatrin, an inhibitor of GABA volve the cornea, lens, or retina. Only groups I and II transaminase, produced retinal degeneration in albino are known to affect retinal functions (Potts, 1996). The Sprague–Dawley rats but no retinal changes in pig- retinal effects need to be distinguished from granular mented Lister-hooded rats (Butler et al., 1987). Fen- deposits in the lens capsule or the corneal endothelium thion, an irreversible cholinesterase inhibitor, induced which have been described in both pigmented and non- adverse retinal effects more rapidly in albino than in pigmented patients, generally after years of treatment.
pigmented Long–Evans rats (Imai, 1975, 1977, 1983).
It is assumed that these deposits are drug-related ma- An antagonist of nicotinamide, 6-aminonicotinamide, terial precipitated from the aqueous humor (Potts, produced more severe ocular damage in nonpigmented than in pigmented rabbits (Render and Carlton, 1985).
The first phenothiazine reported to induce retinal In guinea pigs exposed to ultraviolet light after admin- alterations in humans was the group II phenothiazine istration of 8-methoxypsoralen (8-MOP), iridal and Sandoz NP-207 (Potts, 1996; Kinross-Wright, 1956).
eyelid lesions were far more severe in albino than in Disturbances of the visual function usually developed pigmented animals, probably as a consequence of bind- within 2 to 3 months. The initial symptoms were im- ing of 8-MOP to pigmented tissue (Cloud et al., 1960).
paired adaptation to dim light, followed by more severe In chronic lead retinopathy in rats, pathologic changes visual disturbances and abnormal pigmentation of the in the retina were less severe in pigmented rats than in retina in the form of fine “salt-and-pepper” clumps of a nonpigmented strain (Santos-Anderson et al., 1984).
pigment in the periphery or macula. Total reversal did These observations imply that the presence of melanin not occur and in some cases severe visual loss and may be protective against chemically induced oculotox- blindness resulted. For these reasons, NP-207 was re- moved from clinical study. Thioridazine, an antischizo-phrenia drug also effective for nonpsychotic severeanxiety, was shown to produce a similar pigmentary ALBINO VS PIGMENTED ANIMALS
retinopathy in humans at doses usually in excess of therecommended therapeutic levels. Normal dosage did Toxicity studies are commonly conducted in two lab- not cause retinal damage even after years of treatment oratory animal species, one albino (rodent species) and one pigmented (dog or primate). Since albino animals The group I phenothiazine, chlorpromazine, is gen- do not have melanin in RPE cells or the uveal tract, erally not retinotoxic but is known to produce a revers- questions are periodically raised concerning the suit- ible fine granular pigmentation of the retina in rare ability of albino animals for preclinical testing of drugs.
Although the lack of ocular melanin increases the sen- Phenothiazine retinal toxicity has been studied ex- sitivity of albino rodents to light (e.g., light-dependent perimentally in cats, dogs, and rats (Meier-Ruge and retinopathy), proper husbandry conditions control this Cerletti, 1966; Legros et al., 1971b, 1973). Retinal potential and make the albino rodent as suitable a test changes first occur in the outer segment of the photo- species as any other experimental animal (Rubin and receptor cells, with secondary RPE changes (Heywood, Weisse, 1992). We conclude from the above that clinical 1982). Histologically, there is a vacuolization followed and histopathological examinations performed in toxi- by disorganization and finally atrophy and loss of rods cology studies in the standard pigmented and albino and cones. It has also been shown that phenothiazine animal species are able to demonstrate the absence of derivatives accumulate in very high concentrations in toxic effects in pigmented tissues such as the retina the uveal tract due to melanin binding (Potts, 1996).
(Rubin and Weisse, 1992; Steiner and Buhring, 1990).
However, chlorpromazine causes electroretinographicchanges in both albino and pigmented rats and rabbits(Legros et al., 1973; Jagadesh et al., 1980). Further- CONCLUSIONS
more, since both retinal toxic and nontoxic phenothia-zines bind to melanin, and since no specific activity has The binding of drugs to melanin is a consequence of been identified that is not common to both retinotoxic their physicochemical properties. Approximately 40% and innocuous phenothiazines, the exact mechanism of of drugs are basic and lipophilic, and it is reasonable to this phenothiazine-induced retinal toxicity is not expect that all of them bind to melanin to some extent.
The precedents of chloroquine and phenothiazines,which bind to melanin and also cause retinal toxicity, EVIDENCE THAT MELANIN PROTECTS AGAINST
contribute to the confusion between these two phenom- OCULOTOXICITY
ena, resulting in the misconception that melanin bind-ing is evidence of adverse ocular effects. A review of the Compounds that selectively damage the eye of non- literature shows that melanin binding is not predictive pigmented animals were reviewed by Rubin and ACKNOWLEDGMENTS
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