Stawiski, M., Powell , J., Lang , P., Schork, A., Duell, E. & Voorhees, J. (1975). Papaverine: Its

effects on cyclic AMP in vitro and psoriasis in viva. J. invest. Derm.. 64, 124-127 .

Stawiski, M., Rusin, L., Bums, T., Weinstein, G. & Voorhees, J. (1979). Ro 20-1724: An agent

that significantly improves psoriatic lesions in double-blind c1inical trials. J. invest. Derm ..

73,261-263.

DRUG METABOLISM IN SKIN

M. D. RAWLINSl, S. SHUSTER2, P. H. CHAPMANl,

V. SHAWl & V. A. O'NEILLJ

I Wolfson Unit ofClinical Pharmacology and -Deoartment ofDermatology,

The University,

Newcastle upon Tyne.

England

Human skin is capable of metabolising a variety of drugs and other compounds

(Pannatier, Jenner, Testa & Etter, 1978) (Table I). Our interest has been concerned

particularly, with aryl hydrocarbon hydroxylase (EC 1.14.14.2; AHH), and more

recently with epoxide hydratase (EC.4 .2.1.63; EH) and the hydrolysis of steroid

esters.

Table 1 Drugmetabolism by human skin

Reaction

Oxidation

Epoxidehydratase

Reduction

Hydrolysis

Glucuronidation

Sulphation

Methylation

Glutathioneconjugation

Substrate

Cortisol

Testosterone

Benzo(a]pyrene

Styreneoxide

Cortisol

Progesterone

Diflucortolone valerate

Betamethasone valerate

Aminophenol

Dehydroepiandrosterone

Noradrenaline

Styreneglycol

AHH in human skin has biochemical properties similar to microsomal monooxygenases in other organs (Chapman, Rawlins & Shuster, 1979a); it is inducible in

vitro with benzanthracene; and it is located almost entirely within the epidermis.

Skin EH is also largely (though not exclusively) confmed to the microsomal fraction ,

but is present in both epidermis and dermis (O'Neill, Chapman & Rawlins, 1980).

Hydrolysis of the steroid ester, betamethasone valerate, also occurs in both

epidermis and dermis (Rawlins, Shaw & Shuster, 1979).

Whilst the capacity of human skin to metabolise foreign compounds thus appears

to be considerable, the biological implications remain unexplored. This review

therefore examines the pharmacological, therapeutic and toxicological consequences

ofdrug metabolism in the skin .

DRUG MET ABOLlSM IN SKIN

The skin's contribution to systemic drug metabolism

411

The skin is one ofthe larger human organs (4 kg) with a surface area of2 m-. It has

therefore been suggested that it may contribute significantly to the systemic

metabolism of drugs (Alvares , Kappas, Levin & Conney, 1973; Pannatier et al.,

1978). However, epidermis contributes only 3-5% (120-200 g) of the total. Calculations ofthe total activities of AHH and EH in liver and skin, assuming equivalent

access ofsubstrates into these two organs, indicates that skin AHH and EH activities

represent only 0.2% and 0.5% (respectively) of that in liver (Table 2). It is therefore

unlikely that skin makes a significant overall contribution to systemic drug

metabolism. The possibility still remains that foreign compounds reaching the skin

from the circulation are converted to metabolites with local or systemic activity.

Table 2 Comparison of AHH and EH activities in human skin and liver

Skin Liver

AHH

(nmol 3-hydroxybenzo[a]pyrene formed min- I

)

EH

(IJ mol styrene glycoJ formed min-I

)

0.2

2

132'

1 Estimated from the dat a ofPeikonen (1976)

2 Estimated from the data ofKapitulnik, Levin, Lu, Morecki, Dansette, Jerina & Conney (1977)

The skin as a metabolic barrier to percutaneous absorption

Drugs and the other foreign compounds may reach the systemic circulation by

ingestion, inhalation or percutaneous absorption. The presence of drug-metabolising

enzymes , particularly microsomal monooxygenases, in the liver, gut wall and lung

may serve to protect against absorption oftoxic lipophilic compounds. The physical

properties of skin discourage the percutaneous absorption of hydrophilic

compounds, but lipophilic substances penetrate more readily . It is therefore possible

that drug metabolising enzymes within skin have a protective function , comparable

to that of other organs which are portals of ent ry into the body. In particular, skin

AHH may prevent the systemic absorption of lipophilic polycyclic hydrocarbons.

After topical application to immobilised mice, (14C]-benzo[a]pyrene disappears from

skin with an approximate half-life of6 h (Falk & Kolin, 1963) and the appearance of

radioactivity in the bile is dose-dependent. However, direct evidence to demonstrate

that 'presysternic' metabolism offoreign compounds occurs in skin, as it does in the

liver, is currently unavailable.

Skin metabolism as a determinant of the topical efficacy of drugs

The metabolism of topical drugs within skin could determine efficacy either by

rendering therapeutic agents inactive , or by converting them to biologically active

metabolites.

8etamethasone valerate is effective, when applied topically, in the treatment of a

wide variety of dermatoses. However, the potency of betamethasone-17-valerate

(817) is substantially greater than that of betamethasone-21-valerate (821). In vitro

the apparent rate of hydrolysis of 821 is substantially more rapid than 817 with

appropriate half-lives of2.8 and 22 h respectively (Shaw, Jones , Shuster & Rawlins,

1980). Furthermore, whilst the hydrolysis of 821 occurs enzymatically, the hydrolysis

of 817 apparently involves its non-enzymatic re-arrangement to 821, and this latter

412 M. D. RAWLlNS, S. SHUSTER, P. H. CHAPMAN, V. SHAW & V. A. O'NEILL

step appears to be rate limiting. We have suggested that the difference in the potency

ofthese two esters ofbetamethasone may be due to their relative rates of degradation.

The possibility that the efficacy of other topical drugs is determined by metabolism

within the skin has not been explored, but may be particularly important for the

antipsoriatic properties of dithranol and coal-tars .

Skin metabolism as a determinant oflocal toxicity

Microsomal mono-oxygenases are capable of metabolising a wide variety of

compounds to reactive, electrophilic intermediates which bind to macromolecules

within cells. This process may be important in determining antigenicity (Amos ,

1976), cytotoxicity and carcinogenicity (Geiboin, 1977).

Skin lesions are one of the most common adverse reactions to drugs and some

probably have an immunological basis. lt is possible that covalent binding of drug

metabolites formed within skin may produce haptens, or cause in cytotoxicity, but

evidence for such possibilities is currently lacking.

In both animals, and man, the topical application ofa variety ofpolycyclic hydrocarbons produces skin cancers. The carcinogenicity ofthis diverse group of chemical

substances appears to be determined by activation to yield electrophilic metabolites

(Sims & Grover, 1974; Gelboin, 1977). The carcinogenicity of benzo[a]pyrene

appears to be mediated by benzo[a]pyrene- 7,8-diol -9,10 epoxide (Sims, Grover,

Swaisland , Pal & Hewer, 1974). In vitro human epidermal cells incubated with

benzo[a]pyrene yield benzo[a]pyrene- 7,8-9,IO-diol (Fox, Selkirk, Price, Gray,

Sandford & Cottler-Fox, 1975). AHH and EH thus play an important role in the

activation and detoxiftcation of polycyclic hydrocarbons such as benzo[a]pyrene

(Gelboin, 1977). lt is therefore probable that in human skin that the activities AHH

and EH, as weil as that of glutathione transferase (Mukhtar, 1976)and the presence of

glutathione (Engin, 1976), are important determinants of skin cancers due to soot,

coal tar and oils.

The importance ofskin AHH and EH in the pathogenesis ofskin cancers which are

not so obviously related to chemical exposure, is less certain. However, studies in

animals indicate that polycyclic hydrocarbons act as co-carcinogens with ultraviolet

light, and it is therefore possible that AHH and EH playa much wider role in the

pathogenesis of skin cancer. Our observations in psoriasis would support such a

hypothesis (Shuster, Chapman & Rawlins, 1979). Psoriasis is a chronic disorder

characterised by plaques of abnormal skin whose main feature is an increased rate of

epidermal proliferation. We have reported that the clinically normal, lesion free, skin

of patients with discoid psoriasis has reduced AHH and inducibility (Chapman,

Rawlins & Shuster, 1979b). We have also observed a similar abnormality in the

normal skin of patients with pustular psoriasis (Shuster, Rawlins, Chapman &

Rogers, 1980) which has never been involved in the disease. Psoriasis has been

traditionally treated with a variety of carcinogenic remedies including coal-tar,

arsenic , ultraviolet light and X-rays . Yet the experience of most dermatologists

suggests that skin cancer is rare in psoriasis (Shuster et al., 1979)and this is supported

by limited epidemiological data (Kocsard, 1976).

Skin as a probe for systemic drug metabolism

Studies of drug metabolism in man are often compromised by the necessity to ensure

the health and safety ofthe patients and volunteers taking part. In vitrostudies with

biopsy material, though technically feasible, are usually possible only when tissue is

being obtained for diagnostic purposes. In vivo investigations, involving a careful

DRUG METABOLlSM IN SKIN 413

study of the rate of metabolism of ' rnodel' compounds administered orally or

parenterally, are limited by the toxicity of the particular compound and its

metabolites. Although many 'model' substrates (for example, isoniazid, antipyrine ,

sulphadimidine, acetanilide, paracetamol) can be used safely, suitable chemical

probes for investigating epoxide hydrase, or glutathione transferase are too toxic for

human administration. Skin , which can be easily removed by biopsy or by suction

blister technique, might provide a tissue which could be used to investigate drug

metabolism in less accessible organs. This would require drug metabolising enzymes

in skin to be similar, and under the same genetic and environmental control, to those

in liver and other tissues.

Substantial alterations in the activity of epidermal AHH occur in diseased skin,

and in normal skin with an increased rate of cell division. Furthermore, although we

have been unable to demonstrate differences in AHH activity in a number of skin

sites (Chapman et a/., 1979a) , skin EH activity appears to vary in different regions

(O'Neil et a/., 1980). Moreover, both skin AHH and EH activity increase with age

(Chapman et a/., 1979a ; O'Neill et al., 1980). This contrasts with the age-related

decline in hepatic microsomal oxidation which has been observed with some drugs

(Crooks, O'Malley & Stevenson, 1976). The only direct comparison ofliver and skin

microsomal mono-oxygenase in man, using benzo(a]pyrene as substrate, suggests

th at whilst phenols, quinones and dihydrodiols are formed by both tissues, human

skin (unlike human liver) does not form the K-region epoxide dihydrodiol

(Fox et al.. 1975).

By contrast to these negative fmdings, recent observations in patients with

psoriasis suggest that the activity of AHH in skin may, at least under some circumstances, reflect that in less accessible tissues. We have shown that in psoriasis

antipyrine clearance (Table 3) is reduced in non-smoking psoriatics when compared

to non-smoking age and sex matched controls, though not in psoriatics who smoke

(Chapman, Moss, Keys , Shuster & Rawlins, 1980). The extent to which it is possible

to extrapolate from metabolism in skin to metabolism in other organs therefore

remains uncertain. Further studies, examining specific biochemical pathways, and

carefully controlled for mitotic activity in skin, skin disease, skin site and age are

therefore required.

Table 3 Antipyrine clearance in psoriatics and healthy controls

Non-smokers

Smokers

All

Controls

51.9 ± 2.6"

75.9 ± 5.0

64.2 ± 3.5

Antipyrineclearance

(mI min:')

n Psoriatics

17 4\.9 ± 3.lb

18 73.8 ± 4.9

35 58.3 ± 4.0

n

17

18

35

" SignifIcant (P < 0.01) differencebetweensmokers and non-smokers b Significant(P < 0.01) differencebetweensmokers and non-smokers, and (P < 0.025) between

non-smoking psoriatics and controls

Drug metabolism and skin disease

Diseased skin has altered capacity to metabolise drugs (Kersey, Chapman, Shuster &

Rawlins, 1980). Thus, epidermal AHH is reduced in psoriatic lesions (Chapman et

al., 1979b), and in rapidly dividing normal epidermis (unpublished). Not only may

the 'presystemic' metabolism of topical agents therefore be altered, bu t also the

response to certain therapies and toxicity of metabolites mayaiso change. This may

explain, for example, why the lesions of psoriasis are more resistant to the cytotoxic

effects ofdithranol, than normal skin.

414 M. D. RAWLINS,S. SH UST ER, P. H. CHAPMAN, V.SHAW & V. A. O' NEILL

Conclusions

Whilst drug metabolism in skin probab! y does not contribute sign ifica ntly to

systemic drug metabolism , it may protect against lipophilic en vironmental

pollutants. lt is probably important in determining the efficacy and toxicity ofsome

topical agents, and may provide a valuable tool for in vestigat ing systemic drug

metabolism in man. Further studies ofskin metabolism of drugs in skin disease may

increase our knowledge of the mechanism of action of dermatological drugs, and

indicate a more rational ba sis for their use.

References

Alvares, A. P., Kappas, A., Levin, W. & Conney, A. H. (1973). lnducibility ofbenz(a)pyrene

hydroxylase in human skin by polycyclic hydrocarbons . Clin. Pharmae. Ther..14,30-39.

Amos, H. E. (1976). Allergiedrug reactions. London: Edward Amold .

Chapman, P. H., Moss, C; Keys, B., Shuster, S. & Rawlins, M. D. (1980). Antipyrine clearance

in psoriasis. Brit. med.1., in press.

Chapman, P. H., Rawlins, M. D. & Shuster, S. (l979a). The activit y of aryl hydrocarbon

hydroxylase in adult human skin. Brit. J. clin. Pharmac., 7,499-503 .

Chapman, P. H., Rawlins, M. D. & Shuster, S. (l979b). Activity of aryl hydrocarbon

hydroxylase in psoriatic skin. Lancet, 1,297-298.

Crooks, L, O'Mallcy , K. & Stephenson , I. H. (1976). Pharmacokinetics in the elderly. Clin.

Pharmaeokin., 1,280-296.

Engin, A. (1976). Glutathione content of human skin carcinomas. Areh. Derm. Res., 257,53-55.

Falk, H. L. & Kolin, P. (1963). Chemistry, host entry, and metabolie fate of carcinogens. Clin.

Pharmae. Ther., 4, 88-103.

Fox, C. H., Selkirk, r. K., Price, F. M., Croy, R. G., Sanford, K. K. & Cottler-Fox, M. (1975).

Metabolism of benzet a )pyrene by human epithelial cells in vitro. Cancer Res., 35,

3551-3555.

Gelbo in, H. V. (1977). Cancer susceptibility and carcinogen metabolism. New Eng. J. Med.,

297,384-385.

Kapitulnik, L, Levin, W., Lu, A. Y. H., Morecki, R., Dansettc, P. M., Jerina , D. M. & Conne y,

A. H. (1977). Hydration of arene and alkene oxides by epoxide hydrase in human liver

microsomes. Clin. Pharmac. Ther.. 21, 158-165.

Kersey, P., Chapman, P. H., Shuster, S. & Rawlins, M. D. (1980). Activity of AHH in skin

disease. Scot. med. J., in press.

Kocsard, E. (1976). The rarit y of solar keratoses in psoriatic patients: preliminary report . Aust.

J. Derm.. 17, 65-67.

Mukhtar, H. (1976). Glutathione-S-epoxide transferase in mouse skin and human foreskin. J.

invest. Derm., 66, 161-164.

O'Neill, V. A., Chapman, P. H. & Rawlins, M. D. (1980). Epoxide hydrase activity in human

skin. First World Conference, Clin. Pharmac. Abstract no. 0950.

Pannatier, A., Jenner, P., Testa, B. & Etter, J. C. (1978). The skin as a drug-rnetabolising organ.

Drug.u«.Rev., 8, 319-343.

Pelkonen , O. (1976). Metabolism of benz(a )pyrene in human adult and foeta! tissues. In

Polynuclear Aromatic H ydroearbons: Chemistry. Metabolism and Carcinogenesis, eds.

Freudenthai, R. L. & Jones, P. W., pp. 9-21. New York: Raven Press.

Rawlins, M. 0 ., Shaw, V. & Shuster, S. (1979). The in vitro metabo!ism ofbetamethasone-17-

valerate by human skin. Brit. J. clin. Pharmac.,8, 441P.

Shaw, V. A., Jones, H., Shuster, S. & Rawlins, M. D. (1980). In vitro hydrolysis of betamethasone esters by human tissues. First World Conference Clin. Pharmac . Abstract no.

0476.

Shuster, S., Chapman, P. H. & Rawlins, M. D. (1979). Psoriasis and skin cancer. Brit. med. J.. 2,

941-942.

Shuster, S., Rawlins, M. 0. , Chapman, P. H. & Rogers, S. (1980). Decreased epidermal AHH

and located pustular psoriasis. Brit. J. Derm.. in press.

Sims, P. & Gro ver, P. L. (1974). Epoxides in polycyclic aromatic hydrocarbon metabolism and

carcinogenesis. Adv. Cancer Res., 20, 164-174.

Sims, P., Gro ver, P. L., Swaisland, A., Pal, K. & Hewer, A. (1974). Metabolie activation of

benz(a )pyrene proceeds by a diol-epoxide. Na ture, 252,326-32 8.

UV INFLAMMATION AND

ANTI-INFLAMMATORY DRUGS

M. W. GREAVES

Institute ofDermatology,

Homerton Grove, London, E9. England

The activation ofvitamin D synthesis remains the only weil established physiological

role of ultraviolet radiation (UV) in the skin (Omdahl & de Luca , 1973) although

ultraviolet irradiation has long been apart of dermatological therapy. Harmful

actions include production of inflarnmation, epidermal hyperplasia and carcinomatous changes and degenerative change s in the connective tissue of the dermis.

Interest in the cellular and molecular action of UV in skin has been heightened by a

number of new factors . There is mounting concern about the impact of environmental factors on the amount of solar UV, especially in the shorter wavelength

range , which reache s the earth's surface. The increased use of halogenated hydrocarbon aerosol propellants and refrigerants, and even the advent of supersonic jet

aircraft has led to the prediction that the ozone barrier layer in the stratosphere may

be weakened. Th is, it is claimed, may permit exposure to harmful shorter wavelength

UV , with consequent increased incidence of skin cancer (Goldsmith, Tuck,

Foot, Simmons & Newson, 1973). Greater use is now being made ofultraviolet in the

treatment ofchronic skin disease. In particular, the advent ofphotochemotherapy for

psoriasis which involves oral adm inistration of 8-methoxy psoralen followed by

irradiation with long wavelength UV 365nm (PU VA) (Parrish, Fitzpatrick,

Tanenbaum and Pathak, 1974), has been an important development. Data on the

pathophysiological effects ofUV in human skin is therefore urgently required.

The possible involvement ofprostaglandins in UV erythema was suggested by the

observation that middle wavelength UV (Uv-Bj-induced erythema could be

suppressed by prior administration of the prostagiandin synthetase inhibitor

indomethacin (Eaglestein & Marsico, 1975) although erythema due to PUVA

treatment is resistant to indomethacin (Gschnait & Pehamberger, 1977).