Binding of drugs to eye melanin is not predictive of ocular toxicity
REGULATORY TOXICOLOGY AND PHARMACOLOGY 28, 124 –132 (1998)
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 STRUCTURE OF THE EYE 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-
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). MELANIN BINDING
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-
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-
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-
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
(M. N. G. Dukes, Ed.), 13th ed., pp. 1427–1454. Elsevier Science,Amsterdam.
Frame, S. R., and Carlton, W. W. (1991). Toxic retinopathy, rat,
We record our gratitude to Drs. D. A. Smith, A. Monro, and H. van
mouse, and hamster. In Eye and Ear, Monographs on Pathology of
de Waterbeemd for very helpful discussions and thoughtful com-
Laboratory Animals (T. C. Jones, U. Mohr, and R. D. Hunt, Eds.),
ments. We gratefully acknowledge the help of Laurence Dupont in
pp. 116 –124. Springer-Verlag, Berlin.
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