Pharmac. Ther. Vol. 40, No. I, pp. 123-135, 1989 0163-7258/89 $0.00 + 0.

50
Printed in Great Britain. All rights reserved Copyright © 1988 Pergamon Press pie

Guest Editor: R. M. MACKIE

RETINOID ASSOCIATED PHOTOTOXICITY

AND PHOTOSENSITIVITY

J. FERGUSON and B. E. JOHNSON

Department of Dermatology, University of Dundee, U.K.

INTRODUCTION
Abnormal cutaneous photosensitivity is included among a number of more common
side effects of tretinoin (Fig. 1; all-trans-retinoic acid) (Pedace and Stoughton, 1971;
Papa et al., 1975). The related synthetic retinoids, etretinate (Tigason) and isotretinoin
(Roaccutane) (Fig. 1) may well produce a similar photosensitization. While photo-
sensitivity is frequently listed as an adverse effect of isotretinoin, reports in the literature
are contradictory. An increased susceptibility to sunburn reactions has been stated to occur
in 5-12% of patients (Angel, 1983; Strauss et al., 1984) but the work of others has failed
to detect this problem (Diffey et al., 1985). A single case report of clinical photosensitivity
by McCormack and Turner (1983) described burning erythema of sun-exposed sites which
was thought to be phototoxic in origin. Phototesting a group of subjects taking isotretinoin
proved negative (Diffey et al., 1985).
Etretinate has also been reported as causing sunburn reactions in 7-9% of patients
(Grekin et al., 1984). Two early studies failed to produce evidence of an abnormal response
to sunlight in subjects taking the drug (Ippen et al., 1978; Goerz and Orfanos, 1978) but
case reports continue to appear in the literature (Collins et al., 1986).

D R U G - I N D U C E D PHOTOSENSITIVITY
The true incidence of drug-induced photosensitivity is unknown. It does seem likely that
variations in reported incidence, such as described for chlorpromazine, 16-25 % of subjects
taking the drug (Ayd, 1956; Calnan et al., 1962) or tetracycline, 1-26% (Shapiro and
Phillips, 1961; Orentreich et al., 1961) may be explained by local variations in skin type,
sunlight factors and drug dosage regimens. Nevertheless, it has been our impression that
drugs such as amiodarone, chlorpromazine and benoxaprofen are capable of producing
frequent photosensitization whereas agents such as thiazides and quinine are idiosyncratic,
picking out certain individuals for as yet undefined reasons.
While many drugs have been firmly associated with photosensitivity, many more are
suspected. The Committee on Safety of Medicines adverse reaction reporting system in the
United Kingdom, lists in the region of 250 drugs as possibly producing such an effect.
Unfortunately, only a small number have been studied in detail so that from the literature
sources, firm data are often unavailable to satisfy a number of points essential for patient
management. Such information includes exactly which drugs are responsible for abnormal
skin responses to sunlight, the exact morphology of the reaction produced, the mechanisms
involved in the reactions, the wavelength dependency of the reactions, and long term effects
if observed.

PHOTOSENSITIZATION
Photosensitization may be defined as the action of one component (photosensitizer) of
a system which causes another component (substrate) to be changed by radiation (Lamola,
123
124 J, FERGUSONand B. E. JOHNSON

~ Tretmoin All-trans-retinoicacid
COOH

Ro 1-5488

CH30~ C O O C 2 H 5

Etretinate(Tigason)
• Ro 10-9359
~ O O H
Isotretinoin ( Roaccutane)
Ro 4 - 3780

CHaO~ C O O H

Etretin
Ro 10 - 1670
~ O 4 - Oxo • isotretinoin
OOH

Ro 22 - 6595

C H 3 0 ~ ~ ~ J ~ o o H
Isoetretin
Ro 13-7652
FIG, 1, Retinoids with suspected photosensitizing potential. The molecular structures of all-trans-
retinoic acid and the two synthetic retinoids, etretinate and isotretinoin with their major
metabolites.

1974). It is a process in which reactions to normally ineffective radiation are induced in

a system by the introduction into that system of a specific radiation absorbing substance
(Blum, 1964; Spikes, 1977). For cutaneous photosensitization, the process is usually
considered in terms of normally harmless doses of UVA (315-400 nm) and visible radiation
being absorbed by a "foreign" molecular species at non-damaging concentrations, with
involvement of cell and tissue constituents in the dissipation of the absorbed energy giving
rise to the skin reactions.
Molecular mechanisms of photosensitization vary depending on the structure of the
photosensitizer, the biomolecule with which it becomes associated and whether or not
oxygen is required. Mechanisms at cell and tissue levels also vary. In microorganisms and
more complex cells in culture, photosensitization may give rise to membrane damage,
inhibition of macromolecule synthesis, mutation and cell death, mediated through changes
in target molecules such as protein, lipid and nucleic acids. In skin, immediate or delayed
inflammatory reactions of varying severity resulting directly from these cellular or tissue
reactions are included in a broad category of "Phototoxicity"; where the immune system
is activated, the term "Photoallergy" is used (Epstein, 1939; Harber and Baer, 1972;
Johnson, 1984). Repeated phototoxic insult with certain photosensitizers such as psoralens
may give rise to skin cancer in experimental animals (Epstein, 1977).
In general, phototoxic and photoallergic reactions are harmful to the skin. However, the
principle of phototoxicity is used under controlled conditions and with great benefit in
photochemotherapy (Psoralen + UVA; PUVA) for psoriasis and other dermatoses
(Parrish et al., 1974; Weber, 1980; Morison, 1983) and also in photoradiation therapy for
certain cancers using haematoporphyrin derivatives and other dyestuffs (Dougherty et al.,
1978).
 Retinoid associated phototoxicity and photosensitivity 125

TABLE 1. Photosensitizers
Exogenous Drugs (Table 2)
Plant materials Psoralens, thiophenes, polyacetylenes
Dyestuffs
Thiazines Methylene blue, toluidine blue
Xanthenes Fluorescein, eosin, erythrosin, rose bengal
Anthraquinone based Anthraquinone, benzanthrone disperse blue 35
Pitch, coal tar, wood preservatives Anthracene, acridine, 1,2-benzanthracene
Perfumes and cosmetics Oil of bergamot with 5-methoxypsoralen,
musk ambrette, 6-methylcoumarin
Tatoos Cadmium sulphide
Sunscreens, printing inks
Endogenous Metabolites Porphyrins, kynurenic acid, bilirubin
Normal constituents Tryptophan, riboflavin

PHOTOSENSITIZERS
Photosensitizers producing reactions in the skin may either be exogenous--completely
foreign chemicals which come into contact with the skin by topical or parenteral
administration in an industrial, domestic or therapeutic setting; or endogenous--abnormal
metabolites or normal metabolites in higher than normal concentrations (Table 1). Drugs
(Table 2) and plant materials form the major groups of photosensitizers, but dyestuffs,
polycyclic hydrocarbons in various wood preservatives, perfume and cosmetic con-
stituents, printing inks, sunscreen materials and metal salts contribute to the overall picture
of cutaneous photosensitization.

MECHANISMS OF PHOTOSENSITIZATION
The photochemistry and molecular mechanisms of photosensitization are complex
(Lamola, 1974; Spikes, 1982) but in simple terms, absorption of the appropriate radiation
by a photosensitizer molecule results in a rearrangement of electrons and the ground state
molecule is raised to the excited singlet state. Decay back to the ground state may occur
with the emission of fluorescence or a photochemical change in the molecule may occur
but since the lifetime of the excited singlet is between 10 -9 and 10 -6 sec, photosensitization
involving an interaction with neighbouring molecules is unlikely. Such interactions are

TABLE2. Recognized Photosensitizing Drugs

Antibacterial Tetracyclines Demethylchlortetracycline
Chlortetracycline
Oxytetracycline
Doxycycline
Tetracycline
Sulphonamides
Nalidixic acid
Tranquillizers Phenothiazines Chlorpromazine
Diuretics Chlorthiazides Chlorthiazide
Hydrochlorthiazide
Frusemide
Antiarrhythmics or Amiodarone
Antihypertensives Quinidine
Antidepressants Protriptyline
Non-steroidal anti-inflammatory agents Proprionic acid derivatives Benoxaprofen
Ibuprofen
Naproxen
Azapropazone
Diflunisal
Piroxicam
Antifungal Griseofulvin
Topical bacteriostat or antifungal Halogenated salicylanilides
Bithional
Fentichlor
Hexachlorophene
Buclosamide
Antispasmodics Quinine

J.P.T. 40 I - - I
126 J, FERGUSONand B. E. JOHNSON

/ Excitedsingletstale

f
Photochemistry FI
et state

Photochemistry
Ground state
FIG. 2. Simplifiedschematic for the molecular mechanisms involvedin photochemistry,hv = u.v.
or visible radiation; fl = fluorescence.

more likely following the transition from singlet to the relatively long lived, 10 -3 to,
exceptionally, 100 sec, triplet state (Fig. 2).
It is a general rule that photosensitization proceeds via the triplet state. Although
photosensitizers generally exhibit fluorescence, fluorescent chemicals are not necessarily
photosensitizers. Triplet state formation appears to be better correlated with photosensi-
tizing potential and where complex biological systems are involved, other factors such as
lipid solubility of the photosensitizer and degree of interaction with oxygen become equally
important.
A number of pathways exist for the interactions between triplet state photosensitizer and
the substrate biomolecules.
First, in what are called type I reactions, electron or hydrogen transfer gives rise to
reactive free radical forms of both substrate and photosensitizer. Subsequent reactions vary
but molecular oxygen is commonly involved to produce fully oxidised substrate and
regenerated photosensitizer. Substrate may be oxidised directly by highly reactive super-
oxide, hydrogen peroxide, hydroxyl radicals, products of interactions between free radical
photosensitizer and oxygen, or may become susceptible to oxidation as a result of a
light-induced photosensitizer/substrate complex formation.
Secondly, type II, energy transfer reactions involve the formation of the highly reactive,
excited singlet state of oxygen which may oxidise directly a number of biologically
important substrate molecules.
The majority of photosensitized reactions appear to be oxygen dependent and the term
"Photodynamic Action" is now reserved for these. In addition, however, there are
important oxygen independent reactions, UVA-induced binding of psoralens to DNA
being the best known. Other photosensitizers such as anthracene, alpha-terthienyl and
chlorpromazine may be shown to bind to DNA when irradiated, but this is only one of
a number of photosensitized interactions of these compounds with important biomolecules
and even with the psoralens, singlet oxygen may be formed although the yield is low.
It is clear that for any photosensitizer, the biologic effect may be the result of one or more
preferred pathways rather than a single well-defined reaction. Even so, model systems for
the study of photosensitization at molecule and cellular levels are important to provide a
clear understanding of which of the available reactions may be most important (Johnson
et al., 1986). Phototoxicity is by far the commonest mechanism involved in drug-induced
photosensitization. While drugs have been reported as causing both photoallergy and the
abnormal cutaneous photosensitivity associated with lupus erythematosus and pellagra,
these are rare occurrences.
Although frequently described as a form of "exaggerated sunburn", the presenting
features of phototoxicity are more complex than this (Harber and Bickers, 1981; Johnson,
1984). They range from an immediate prickling, burning sensation with erythema to
delayed onset erythema or even increased skin fragility and blistering (Table 3). Chronic
effects are drug specific ranging from hyperpigmentation, which may be golden brown or
slate-grey to purple in colour, as induced by amiodarone (Vos et al., 1972) or chlor-
promazine, (Satanove, 1965) to photoonycholysis with benoxaprofen (Hindson et al., 1982)
demethylchlortetracycline (Orentreich et al., 1961) or psoralens (Rau et al., 1978) and milia
following severe benoxaprofen photosensitization (Stuart, 1982). Although in general,
photosensitivity does not persist beyond one or two weeks after cessation of drug therapy,
there have been occasional reports of photosensitivity reactions persisting for many
 Retinoid associated phototoxicity and photosensitivity 127

TABLE3. Cutaneous Phototoxicity

Skin reactions Photosensitizers or diseases
Prickling and burning; immediate erythema; oedema Coal tar, pitch, anthraquinone based dyestuffs beno-
or urticaria with higher doses. Sometimes delayed xaprofen, amiodarone, chlorpromazine, haemato-
erythema and hyperpigmentation porphyrin, erythropoieticprotoporphyria
Exaggerated delayed erythema Drugs such as demethylchlortetracycline,thiazides,
quinine
Late onset erythema, blistering with slightly higher Psoralens, phytophotodermatitis,berlock dermatitis
exposures, low exposure doses may lead to hyper-
pigmentation only
Increased skin fragility, blistering with friction or Nalidixic acid, frusemide, porphyria cutanea tarda
trauma
Lichen planus like Quinine

months. Such a persistent effect was reported in a subject taking oxytetracycline after 5-6
months (Tromovitch and Jacobs, 1963) and in subjects treated with thiazides with
problems continuing for months to years after stopping the drug (Robinson et al., 1985).
The mechanisms involved in this persistence of photosensitivity are unknown but may
include idiosyncratic pharmacokinetic factors such as the retention of photoactive
metabolites.

RETINOID-INDUCED PHOTOSENSITIVITY
It is against this, in some instances, ill-defined background of clinical and laboratory
studies that retinoid-induced photosensitization should be considered. A prerequisite for
any photochemical reaction is that u.v. or visible radiation is absorbed. This is the first
law of photochemistry and it applies equally to photosensitization. The retinoids obviously
exhibit this prerequisite as illustrated by the absorption spectra of tretinoin (Fig. 3) and
etretinate (Fig. 4), typical of the different compounds of interest, in which the major
absorption is in the ultraviolet wavelength range between 280 and 400 nm, popularly
known as the UVB (280-315 nm) and UVA (315-400 rim). A major feature of the data
sheet for these compounds is the fact that they are denatured by exposure to sunlight.
It would therefore appear that all retinoids are photochemically active. This is not
surprising since 11-cis-retinal (11-cis-vitamin A aldehyde), a close derivative of retinoic
acid, is the major light absorbing compound (chromophore) in rhodopsin, the visual

1.0
0.9
0.8
~ COOH

0.7
0.6
0.5
0.4
0.3
0.2
0.1
P I
275 300 325 350 400 450
Wavelength( nm )
FIG. 3. Ultraviolet absorption spectrum of tretinoin. Approximately 5#g/ml in Dimethyl-
sulphoxide.
128 J. FERGUSONand B. E. JOHNSON

1.0 o ~ C O O C 2 Hs
0.9
0.8 CHa
0.7
8 0.6
0.5

0.4

0.3

0.2

0.I
l l l I l
275 300 325 350 400 450
Wavelength( nm )
FIG. 4. Absorption spectrum of etretinate. Approximately 5 #g/ml in Dimethylsulphoxide.

pigment in animals (Dratz, 1977). The photochemistry of 11-cis-retinal is centred on an

isomerization to the all-trans form of the molecule. It is probable that vitamin A itself and
particularly vitamin A acid would be susceptible to similar photoisomerization. However,
relatively little is known about the photochemistry of retinoic acid itself in the all-trans
form or, as isotretinoin, the 13-cis-isomer, or about etretinate. Simple studies have shown
that etretinate in solid form is denatured by around 27% to give a mixture of cis/trans
isomers and dimers while in ethanol solution, an equilibrium of isomers is obtained in
which the all-trans form represents only some 10%. For isotretinoin, a similar photo-
isomerization occurs leading to a 75% reduction in the 13-cis form (Patel, 1987). For both
retinoic acid (all-trans) and retinaldehyde a low but significant quantum yield of triplet
state formation may be obtained (Lo et al., 1982). Photosensitization might therefore be
expected with these compounds. The chemical structures of isotretinoin (13-cis-retinoic
acid) and etretinate are not so different and similar triplet yields might be expected. These
aspects of retinoid photosensitization remain to be investigated.

CLINICAL STUDIES
Following the diagnosis of clinical photosensitivity in one ichthyosis patient taking
etretinate, we studied this patient and 8 others, the majority with psoriasis, who had been
taking etretinate, 10-50 mg/day, for 3-12 months (Table 4). Six subjects with acne, taking
isotretinoin, 10-30 mg/day for a minimum of 4 months were also investigated (Table 5)
(Ferguson and Johnson, 1986).
All subjects were questioned and examined for features of photosensitivity. None
was taking any other systemic medication and none had a previous history of a photo-
dermatosis.
Each subject was phototested on the skin of the upper back using a 150 W xenon arc
solar simulator (Johnson and Mackenzie, 1982) filtered to provide whole spectrum
radiation (wavelengths greater than 280 nm) or whole spectrum minus UVB (wavelengths
greater than 315 nm) to obtain a preliminary indication of abnormal photosensitivity and
a diffraction grating monochromator with a 1.6 kW xenon arc source to obtain more
clearly defined action spectra (Mackenzie and Frain-Bell, 1973). Minimal erythema dose
(MED) determinations were performed by exposing skin areas, 8 mm in diameter, to a
succession of radiation doses selected from a geometric series with incremental steps
of approximately 20%. Any erythema reactions were recorded immediately after the
 Retinoid associated phototoxicity and photosensitivity 129

TABLE 4. Clinical Features of Subjects Taking Etretinate

Daily Duration of
Age Skin dosage treatment Clincal
Subject Sex (years) type Diagnosis (mg) (months) photosensitivity
1 F 41 I Psoriasis 30 7 No
2 M 57 IV Psoriasis 30 6 No
3 M 57 I Psoriasis 10 4 No
4 M 63 I Pityriasis rubra pilaris 30 11 No
5 M 69 IV Psoriasis 25 6 No
6 M 60 II Psoriasis 50 9 No
7 F 42 II Psoriasis 50 3 No
8 F 41 II Psoriasis 50 12 No
9 M 31 I Ichthyosis* 50 3 Burning erythema
*Non-bullous ichthyosiform erythroderma.

exposures, continuously during the first hour and thereafter at 2, 4, 6 and 24 hr, some
subjects also being examined at 48 hr.
Of the 9 subjects taking etretinate, one (subject 9, Table 4) who had a tendency to
sunburn without tanning (skin type I) before taking the drug, noted a worsening skin
response to sunlight, in that within 3 weeks of starting etretinate (1 mg/kg) he developed
a recurrent and uncomfortable erythema on the skin exposed to direct sunlight. Within
2 weeks of stopping the drug, his skin response to sunlight returned to normal. The other
8 subjects had no abnormal clinical photosensitivity. For the 6 subjects taking isotretinoin,
clinical histories showed no evidence of an increased susceptibility to sunburn or any
abnormal responses to sunlight (Table 5). The results of phototesting were compared with
those of a known normal population. Of the 9 subjects taking etretinate, 6 responded
normally while two (subjects 8 and 9) produced abnormal delayed erythema responses in
that the MEDs for whole spectrum solar simulator radiation were lower than normal
(Table 6). The MEDs for whole spectrum minus UVB were normal, indicating that any
abnormal photosensitivity should involve the UVB wavelengths. For these two subjects,
monochromator testing produced lower than normal MEDs for wavelengths from
295 + 5 nm through 365 + 30 nm with the increased sensitivity most pronounced between
305 and 320 nm (Table 6). Subject 9 stopped taking etretinate, and, one month later,
phototesting results were normal apart from a borderline sensitivity at 335 + 30 nm.
An unusual immediate erythema reaction, persisting for longer than 5 min and not seen
in normal subjects, was obtained in one subject (subject 3) with 12.0 J/cm 2 at 365 + 30 nm
and with 47 J/cm 2 at 400 _ 30 nm.
The phototesting results for 5 of the 6 subjects taking isotretinoin were within normal
limits. However, subject number 3 in this group produced reactions at the lowest level of
normal values for wavelengths 310 and 315 nm and below this at 320 nm. Even so, this
did not appear as a remarkable example of abnormal photosensitivity.

LABORATORY STUDIES
Numerous in vitro tests are available to screen the phototoxic potential of chemicals and
to study their mode of action. We have used 3 model systems to examine various aspects

TABLE 5. Clinical Features of Subjects with Acne Vulgaris Taking Isotretinoin

Daily Duration of
Age Skin dosage treatment Clinical
Subject Sex (years) type (rag) (weeks) photosensitivity
1 M 24 III 30 10 No
2 M 20 II 10 12 No
3 M 19 III 10 8 No
4 M 19 II 30 24 No
5 M 22 II 20 4 No
6 M 22 III 40 7 No
No subject showed signs of milia, onycholysis, or abnormalities of pigmentation.
 TABLE 6. Minimal Erythema Dose (MED ) Determinations for Abnormal Delayed Reactions in Subjects Taking Retinoids
Solar simulator Monochromator
Waveband (J/cm 2) Waveband + 5 nm (mJ/cm2) Waveband + 30 n m (J/cm 2)
> 280 nm > 315 nm 295 300 305 310 315 320 330 335 365 400 430
Etretinate
Subject 8 4* 100 3.3* 1.5" 1.5" 3.3* 15" 33* 220* 0.82* 6.8* >47 >82
z
Subject 9 2* 100 6.8 3.9* 1.5" 3.9* 68* 180" 1200" 1.8" 4.7* >47 >82 g0
Subject 9a** NT NT 10 NT > 19 NT NT 1200 NT 1.5" > I0 >47 NT e~
lsotretinoin
Subject 3 10 > 100 >8.2 18 >33 150 560 680* >2200 >2.2 > 10 >47 >82
Lowest M E D in normals 7 100 6.8 15 22 150 560 820 2200 2.2 8.2 >47 >82
NT: not tested. Z
*Abnormal response dose.
**Subject 9a was subject 9 tested again 1 m o n t h after stopping etretinate treatment.
For subjects 1-7 taking etretinate and subjects l, 2, 4, 5 and 6 taking isotretinoin, the M E D s each waveband were equal to, or greater by one or more steps in the exposure
series than, the lowest M E D in normals shown here.
 Retinoid associated phototoxicity and photosensitivity 131

of the actions of all-trans-retinoic acid, etretinate and its metabolites, etretin and isoetretin,
and isotretinoin and its metabolite, 4-oxo-isotretinoin.
Photohaemolysis (Hetherington and Johnson, 1984), the photosensitized release of
haemoglobin from washed red blood cells in dilute suspension, was obtained with
all-trans-retinoic acid and both isotretinoin and its 4-oxo-metabolite. Although etretinate
was not effective in this test, etretin, its carboxylic acid first major metabolite, was
phototoxic (Fig. 5). In preliminary studies, the 13-cis-isomer of etretin, the second major
metabolite, was also active but to a lesser extent. A phototoxic index, based on the
concentration of drug required to produce 50% haemolysis with a standard exposure to
UVA (12.2 J/cm 2) shows a descending order of etretin, all-trans-retinoic acid, isotretinoin
and 4-oxo-isotretinoin (Table 7). In this kind of test, isoetretin is approximately half as
effective as etretin. Similar results were obtained using human lymphocytes in short term
culture. In this model, phototoxicity is assessed by the inhibition of tritiated thymidine
uptake by the lymphocytes after stimulation with PHA. Etretinate again proved to be
non-phototoxic but etretin and isoetretin were positive. For etretin, the concentration of
drug required to produce phototoxicity was an order of magnitude less than for
photohaemolysis (Fig. 6), 0.3 #g/ml producing 50% inhibition. It may be inferred from
this result that some intracellular target, rather than the cell membrane itself, is involved
in the response to etretin photosensitization. In this model, isotretinoin was relatively

(a) 100 .~-----g.-~---- • ~

75

E
0
50

25

I
500 1000 1500 2000""~ 3680
7360
Concentration v.g %

(b) 100

75

.3
o
50

25
/
I I I I
2000 4000 6000 8000
Concentration tzg %
FIG. 5. Photohaemolysis with the retinoids and U V A dose of 11.52 J/cm 2. (a) x = etretinate;
• = etretin; + = tretinoin. (b) isotretinoin.
132 J. FERt3USOSand B. E. JOHNSON

TABLE7. Photohaemolysis with Retinoids:

Concentration Required for 50% Haemo-
lysis with a Standard UVA Exposure Dose
of ll.52J/cm 2 (HDso)
Retinoid HD so ~ug%)
Etretin 300
Tretinoin 460
Isotretinoin 2,300
4-oxo-isotretinoin > 14,720
Etretinate no haemolysis

toxic in the dark at concentrations above 0.4/~ g/ml but a greater effect was obtained with
exposure to UVA. With the 4-oxo-metabolite, only phototoxicity was obtained with
concentrations from 0.4-2.0/~g/ml. All-trans-retinoic acid was phototoxic with concen-
trations above 0.2/~g/ml, again, an order of magnitude or so less than required for
photohaemolysis.
With the simple microbiological test devised by Daniels (1965) using Candida albicans,
we were unable to demonstrate a phototoxic potential for any of the retinoids. This may
be due to an inability to penetrate the yeast cell wall.

DISCUSSION
Although our investigations have confirmed previous findings that abnormal cutaneous
photosensitivity due to systemic retinoids is rare, we have obtained evidence on clinical
grounds and with controlled phototesting that it does occur. Moreover, we have shown
that these compounds or their metabolites do have a phototoxic potential.
The case of etretinate-induced photosensitivity which was accompanied by positive
phototest results from 300 nm to 365 nm with virtual clearance after stopping the drug,
is strong evidence for a photosensitizing action. The clinical reaction of a burning erythema
in the skin exposed to sunlight is typical of one form of phototoxicity. The two subjects
who were demonstrated to be photosensitive by phototesting could not be distinguished
from the other subjects taking etretinate by skin type, drug dosage or duration of
treatment. This suggests an idiosyncratic reaction which might be explained in terms of
individual variation in the metabolism and/or pharmacokinetics of the drug. The
persistence of residual photosensitivity in one subject for one month after stopping the
drug fits well with the long half-life of the drug (Rollman and Vahlquist, 1983).
It is clear from the in vitro studies that all-trans-retinoic acid may be photo-
sensitizing in its own right. Although etretinate itself is non-photosensitizing, the drug
may produce cutaneous photosensitization through its first major metabolite. Isotretinoin

+1
.~ 100
~. 90
~ 80
/
! I/
"" 70
~ 60
~ 50
~ 4o
N 30
~ 2o
:--" 10
o
1.0 2.0 3.0 4.0 5.0 6.0 710 810 910 101.0
Etretin concentration(/~g[ rrd )
FIG. 6. Photosensitized and dark control inhibition of PHA stimulated 3H-thymidineuptake in
lymphocytes with etretin. UVA exposure dose: 11.52J/cmg . . . . UVA exposed; - - dark.
 Retinoid associated phototoxicity and photosensitivity 133

may be photosensitizing itself, but here again reactions may also be due to a phototoxic
metabolite.
We have reported previously that desethylamiodarone, the major metabolite of
amiodarone, has a greater phototoxic potential than that of the parent drug (Ferguson
et al., 1985). Similar observations have been reported for chlorpromazine and its
demethylated metabolites (Ljunggren and M611er, 1977). The finding that etretinate has
no phototoxic potential while its major metabolite, the carboxylic acid which is similar
in structure to all-trans-retinoic acid, is photoactive appeared to be unique for drug
induced phototoxicity. However, a similar explanation for phototoxicity due to the
non-steroidal anti-inflammatory drug, Piroxicam, has recently been reported (Kochevar
et al., 1986).
The lack of unequivocal evidence of photosensitivity due to isotretinoin in our study
appears at variance with the findings of a phototoxic potential in vitro and also with reports
from the USA. However, the subjects in our study were on lower doses of isotretinoin than
used in the USA where there may be an additional factor of increased levels of sunlight.
Anecdotal reports of photosensitivity due to isotretinoin may also be related to higher
levels of both drug and sunlight. Even so, the inference should be drawn that the relative
rarity of photosensitivity due to isotretinoin depends, as with etretinate, on individual
variation in the metabolism and pharmacology of the drug since it would seem that given
a sufficient concentration of the drug in the skin and exposure to appropriate radiation
levels, phototoxic reactions should occur in everyone. While the clinical and laboratory
studies seem to indicate that the abnormal photosensitivity associated with etretinate is
due to phototoxicity, an alternative hypothesis exists in terms of the known etretinate-
induced thinning of the stratum corneum with a subsequent increase in the transmission
of u.v. radiation. However, complete removal of the stratum corneum results in only a
3-fold increase in photosensitivity (Claesson et al., 1959; van der Leun, 1966) whereas
we obtained MEDs lowered by an order of magnitude or more. In addition, against
this explanation, the other subjects on retinoid therapy experienced the dryness and
increased fragility typical of adverse epidermal effects which might have been expected to
result in abnormal photosensitivity if this were the mechanism involved. Photohaemolysis
with the retinoids was obtained using UVA wavelengths from 315-400 nm, the peak
emission from the lamps being around 355 nm. Preliminary studies of the wavelength
dependence for this reaction with etretin showed a wide action spectrum around a peak
at 330 nm but extending well beyond 360nm. With isoetretin, the major effective
wavelengths appeared to be around 380 nm. It is clear that if the photosensitivity due
to etretinate is in the main caused by etretin, the shorter UVA wavelengths are most
effective. However, longer wavelengths may also play a part through etretin itself and also
through isoetretin. Where phototesting was positive in the etretinate treated subjects, a
broad spectrum of photosensitivity was obtained. Accordingly, the one subject is our
series with a clinical photosensitivity associated with etretinate, who restarted the
drug, used broad spectrum photoprotection, sunscreening clothing and a zinc oxide
containing sunscreen. These measures produced an apparent reduction in the photo-
sensitivity problem.
It is clear that etretinate may induce abnormal cutaneous photosensitivity in some
subjects and isotretinoin may also have this effect. We have established that the metabolites
of etretinate and both isotretinoin and its major metabolite have a phototoxic potential
which may explain the considerable numbers of anecdotal reports of photosensitivity
accompanying the use of retinoids in dermatologic therapy.

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