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Gaining more insight into the pathomechanisms of thiol-induced acantholysis
Medical Hypotheses (1997) 48, 107-110
© Pearson Professional Ltd 1997
Gaining more insight into the pathomechanisms of thiol-induced acantholysis R. WOLF*, V. RUOCCOt *Macabbi Health Care Outpatient Clinic, and Sackler Faculty of Medicine, TeI-Aviv University, TeI-Aviv, Israel; tDepartment of Dermatology, University of Naples II, School of Medicine and Surgery, Naples, Italy (Correspondence to Ronni Wolf MD, 13 Joseph Hanassi Street, TeI-Aviv 65236, Israel. Fax: (+972) 9 560978)
Abstract - - Acantholysis is considered the initial and the main pathogenetic event of pemphigus. The first step in drug-induced acantholysis (biochemical and/or immunological) involves binding of the drug to the cell membrane and the formation of 'drug-cysteine' instead of 'cysteine-cysteine' bondings. We suggest that the reaction of D-penicillamine with cystine disulfides that results in cysteine-penicillamine disulfides is not a terminal reaction, but rather a primary initiating step of a chain reaction. It is reasonable to consider that the cysteine-penicillamine disulfide is continuing to be enzymatically reduced by various thiol reductants, in particular glutathione reductase, thereby generating a 'new' penicillamine molecule which, in turn, reacts with other cystine disulfides and does so in an unending cycle. A chain reaction is thus created in which the drug is repeatedly generated so that one molecule of the drug may attack thousands of cystine disulfide bonds. It is highly possible that normal individuals have their own endogenous means of controlling this deleterious chain reaction, whereas pemphigus-prone individuals lack the ability to stop this potentially damaging reaction. Drug-induced pemphigus should thus be added to the ever-growing list of adverse drug reactions related to pharmacogenetic disorders in drug metabolism.
Acantholysis provoked in vitro Acantholysis is a morphofunctional change of Malpighian epithelia that results in the loss of intercellular cohesion and halts the process of keratinization. Authors" note: The opinions expressed herein are solely those of
the writers and do not necessarily reflect the opinions of the institutions with which the writers have been associated.
Although acantholytic changes may be seen in numerous and heterogenous clinical conditions, they are considered to comprise the hallmark, the initial and the main pathogenetic event of pemphigus. Acantholysis can be produced experimentally, both in vivo and in vitro, by culture of human skin explants with the addition of different substances which alter the keratinocyte's biochemical homeostasis (1-8). The pioneering studies on the subject were performed
Date received 16 April 1996 Date accepted 16 May 1996 107
108
MEDICAL HYPOTHESES
in 1956 by Stoughton and Novak (9), who demon- ference by antigen modification, caused by the drug strated the disruption of tonofibrils and so-called and possibly eliciting autoantibody production (1). 'intercellular bridges' by disulfide-splitting agents The fact that several reported cases of drug-induced such as cysteine and reduced glutathione. This ob- pemphigus did not show tissue-bound or circulating servation was made long before the first report of intercellular antibodies, whereas others did (12,13), drug-induced pemphigus by Degos et al in 1969 (10). indicates that the two above-mentioned mechanisms The striking structural similarities between cysteine (a and b) might play a role in the development of the and penicillamine, together with the fact that the latter disease, either together or individually. may induce pemphigus, led to the speculation that it It is noteworthy that the primary step of drugmay cause acantholysis as well. Indeed, Ruocco et al induced acantholysis is the same for these two (3) demonstrated that the addition of D-penicillamine mechanisms and it is this biochemical step that we to normal human skin specimens caused acantholytic will address and offer a modification to the tradisplitting (biochemical acantholysis) very similar to tional and well-established concept of what are the that produced by pemphigus serum (immunologic dynamics of the disease process. acantholysis). The first step in drug-induced acantholysis (bioFurther experiments were then carried out by chemical and/or immunological) involves binding of different teams (1-8) to verify the in vitro acan- the drug to the cell membrane and the formation tholytic property of both natural (cysteine, reduced of 'drug--cysteine' instead of 'cysteine-cysteine' glutathione) and medicamentous thiols, such as bondings (Fig., Reaction 1). These newly formed penicillamine, captopril, thiopronine and piroxicam, anomalous disulfides are inadequate to the normal and recently, nutritional factors (11). cell-cell adhesion (based on cystine disulfide bonds), Those experiments revealed that, in addition to thus resulting in dyshesion between keratinocytes that the specific type of thiol added to the specimen, its subsequently leads to acantholysis with no immune concentration and time of action, the intensity of mediation. Alternatively, the anomalous disulfides in vitro acantholysis also depends upon the indivi- may lead to a change in the conformation of these dual susceptibility of the skin-donor. Moreover, they cell-surface antigens, rendering them immunogenic proved that thiol drugs are able to provoke acantho- with a resultant autoantibody formation (reviewed lysis without antibody mediation, a phenomenon that in Ref. 1). has been termed 'biochemical acantholysis', and that, Today, it is generally accepted that the primary again, susceptibility to the acantholytic effect of drugs target of D-penicillamine action is the cystine varies from person to person (4,11). disulfide bonds leading to the formation of cysteineOn the whole, a variety of heterogenous factors, penicillamine mixed disulfides (Fig., Reaction 1). such as inherited gene disorders (Hailey-Hailey), This chemical reaction is probably responsible for the intercellular antibodies (idiopathic pemphigus), and drug's action and also for its side-effects (1,14-18). drugs (mainly thiol drugs) may all interfere with cell-cell adhesion, resulting in acantholysis. As to pemphigus, it is generally accepted that the onset A proposed addition to the established reaction: and, above all, the progress of the disease depends the initiation of a chain reaction on a variable interaction of endogenous (genetic and autoimmune) and exogenous (inducing) factors. We suggest that the reaction of D-penicillamine Genetic predisposition alone ('the soil') is certainly with cystine disulfides that results in cysteineessential, although not in itself sufficient for causing penicillamine disulfides is not a terminal reaction, an outbreak of pemphigus; the intervention of exo- but rather a primary initiating step of a chain reaction. genous, heterogenous factors ('the seed') often appears It is reasonable to consider that the cysteineto be no less decisive in triggering and activating the penicillarnine disulfide is continuing to be enzymatifull-blown disease. cally reduced by various thiol reductants, in particular glutathione reductase, thereby generating a 'new' penicillamine molecule which, in turn, reacts with Pathogenic hypotheses on thiol-induced other cystine disulfides and does so in an unending acantholysis cycle (19) (Fig., Reaction 2). A chain reaction is thus created, in which the drug is repeatedly generated Although the mechanisms involved in drug-induced so that one molecule of the drug may attack thousands acantholysis are not well understood, two hypotheses of cystine disulfide bonds. This reaction may continue have been proposed: (a) direct biochemical drug uninterruptedly until it is interfered with by other interference with keratogenesis; and (b) indirect inter- external factors. It is highly probable that normal
109
PATHOMECHANISMS OF THIOL-INDUCED ACANTHOLYSIS
Reaction 1
KS-SK
+
P-SH
-~ K S - S - P
+
K-SH
Reaction 2
KS-S-P
Fig.
Reductase
K-SH
+ P-SH KS-SK
= cysteine disulfide b o n d
P-SH
= penicillamine
Possible biochemical reactions in thiol-induced acantholysis.
individuals have their own endogenous means of controlling this deleterious chain reaction, whereas pemphigus-prone individuals lack the ability to stop this potentially damaging reaction. There are many other examples of genetic differences in drug-metabolizing enzymes that are associated with adverse drug-reactions in susceptible individuals (20). Well-known examples of adverse drug-reactions related to pharmacogenetic disorders in drug metabolism are: (1) Procainamide- and hydralazine-induced lupus erythematosus related to slow acetylation (21); (2) sulphonamide- and anticonvulsant-induced hypersensitivity syndromes, probably associated with a defect in the detoxification of oxidative metabolites of the drug (22,23); and (3) perhaps the best-known and classic example is glucose-6-phosphate dehydrogenase deficiency and susceptibility of the red blood cells to oxidizing drugs. We believe that such a chain reaction may effectively explain the high reactivity of the thiol drugs and their ability to cause extensive acantholysis even at low concentrations. We recognize that it would be overly simplistic to assume that the reactions described above are the only ones involved in this process. The actual molecular and biochemical events are more likely to be manifold and complex, and the myriad of combined, additive, synergistic and antagonistic effects are boundless. It is our conviction, however, that we have gained some more insight into the basic biochemical reactions involved in this disease process. It is our hope that, with the recent advances in molecular biology, it will be possible in the future to phenotype people who are
unable to control the deleterious chain reaction outlined here. Preventing these susceptible individuals from exposure to certain drugs, such as penicillamine, might then prevent the appearance of the disease. References 1. Ruocco V, de Angelis E, Lombardi M L. Drug-induced pemphigus. II. Pathomechanisms and experimental investigations. Clin Dermatol 1993; 11: 507-513. 2. Ruocco V. L'acantolisi in vivo ed in vitro. Ann Ital Dermatol Clin Sper 1993; 47: 29--40. 3. Ruocco V, de Luca M, Pisani M et al. Pemphigus provoked by D-penicillamine. An experimental approach using in vitro tissue cultures. Dermatologica 1982; 164: 236-248. 4. Ruocco V, de Angelis E, Lombardi M L. In vitro acantholysis by captopril and thiopronine. Dermatologica 1988; 176: 115-123. 5. Yokel B K, Hood A F, Anhalt G J. Induction of acantholysis in organ explant culture by penicillamine and captopril. Arch Dermatol 1989; 125: 1367-1370. 6. Ruocco V, Pisani M, de Angelis E et al. Biochemical acantholysis provoked by thiol drugs. Arch Dermatol 1990; 126: 965-966. 7. De Dobbeleer G, Godfrine S, Gourdain J M e t al. In vitro acantholysis induced by D-penicillamine, captopril and piroxicam on dead de-epidermized dermis. J Cutan Pathol 1992; 19: 181-186. 8. Hashimoto K, Singer K, Lazarus G S. Penicillamine-induced pemphigus. Arch Dermatol 1984; 120: 762-766. 9. Stoughton R B, Novak N. Disruption of tonofibrils and intercellular bridges by disulfide-splitting agents. J Invest Dermatol 1956; 26: 127-136. 10. Degos T, Touraine R, Blaich S, Revuz J. Pemphigus chez un malade trait6 par penicillamine pour maladie de Wilson. Bull Soc Fr Dermatol Syphilogr 1969; 76:751-753. 11. Brenner S, Ruocco V, Wolf R, De Angelis E, Lombardi M L. Pemphigus and dietary factors. In vitro acantholysis by allyl
110
12. 13. 14.
15.
16. 17.
MEDICAL HYPOTHESES
compounds of the genus Allium. Dermatology 1995; 190: 197-202. Wolf R, Tamir A, Brenner S. Drug-induced versus drugtriggered pemphigus. Dermatologica 1991; 182:207-210. Wolf R, Brenner S. Arzeneimittelbedingter Pemphigus. Ubersicht. Z Hautkr 1990; 66: 289-293. Howard-Lock H E, Lock C J L, Mewa A, Kean W F. Dpenicillamine: chemistry and clinical use in rheumatic disease. Sem Arthr Rheum 1986; 15: 261-281. Yu T F, Roboz J, Johnson S, Kaung C. Studies on the metabolism of D-penicillamine and its interaction with probenecid in cystinuria and rheumatoid arthritis. J Rheumatol 1984; 11: 467-470. Huck F, de Medicis R, Lussier A, Dupuis G, Federlin P. Reducing property of some slow acting antirheumatic drugs. J Rheumatol 1984; 11: 605~09. Korman N J, Eyre R W, Zone J, Stanley J R. Drug-induced pemphigus: autoantibodies directed against the pemphigus antigen complexes are present in penicillamine and captopril-
induced pemphigus. J Invest Dermatol 1991; 96: 273-276. 18. Ruocco V, Pisani M. Induced pemphigus. Arch Dermatol Res 1982; 274: 123-140. 19. Drummer O H, Routley L, Christophidis N. Reversibility of disulfide formation. Comparison of chemical and enzymemediated reduction of penicillamine and captopril disulfides. Biochem Pharmacol 1987; 36:1197-1201. 20. Shear N H, Bhimji S. Pharmacogenetics and cutaneous reactions. Sem Dermatol 1989; 8: 219-226. 21. Breathnach S M, Hinter H. Lupus erythematosus (LE)-like syndrome induced by drugs. In: Breathnach S M, Hinter H, eds. Adverse Drug Reactions and the Skin. Oxford: Blackwell Scientific, 1992:113-118. 22. Shear N H, Speilberg S P, Grant D M e t al. Differences in metabolism of sulfonamides predisposing to idiosyncratic toxicity. Ann Intern Med 1986; 105: 179-184. 23. Shear N H, Speilberg S P. Anticonvulsant hypersensitivity syndrome. In vitro assessment of risk. J Clin Invest 1988; 82: 1826-1832.
© Pearson Professional Ltd 1997
Gaining more insight into the pathomechanisms of thiol-induced acantholysis R. WOLF*, V. RUOCCOt *Macabbi Health Care Outpatient Clinic, and Sackler Faculty of Medicine, TeI-Aviv University, TeI-Aviv, Israel; tDepartment of Dermatology, University of Naples II, School of Medicine and Surgery, Naples, Italy (Correspondence to Ronni Wolf MD, 13 Joseph Hanassi Street, TeI-Aviv 65236, Israel. Fax: (+972) 9 560978)
Abstract - - Acantholysis is considered the initial and the main pathogenetic event of pemphigus. The first step in drug-induced acantholysis (biochemical and/or immunological) involves binding of the drug to the cell membrane and the formation of 'drug-cysteine' instead of 'cysteine-cysteine' bondings. We suggest that the reaction of D-penicillamine with cystine disulfides that results in cysteine-penicillamine disulfides is not a terminal reaction, but rather a primary initiating step of a chain reaction. It is reasonable to consider that the cysteine-penicillamine disulfide is continuing to be enzymatically reduced by various thiol reductants, in particular glutathione reductase, thereby generating a 'new' penicillamine molecule which, in turn, reacts with other cystine disulfides and does so in an unending cycle. A chain reaction is thus created in which the drug is repeatedly generated so that one molecule of the drug may attack thousands of cystine disulfide bonds. It is highly possible that normal individuals have their own endogenous means of controlling this deleterious chain reaction, whereas pemphigus-prone individuals lack the ability to stop this potentially damaging reaction. Drug-induced pemphigus should thus be added to the ever-growing list of adverse drug reactions related to pharmacogenetic disorders in drug metabolism.
Acantholysis provoked in vitro Acantholysis is a morphofunctional change of Malpighian epithelia that results in the loss of intercellular cohesion and halts the process of keratinization. Authors" note: The opinions expressed herein are solely those of
the writers and do not necessarily reflect the opinions of the institutions with which the writers have been associated.
Although acantholytic changes may be seen in numerous and heterogenous clinical conditions, they are considered to comprise the hallmark, the initial and the main pathogenetic event of pemphigus. Acantholysis can be produced experimentally, both in vivo and in vitro, by culture of human skin explants with the addition of different substances which alter the keratinocyte's biochemical homeostasis (1-8). The pioneering studies on the subject were performed
Date received 16 April 1996 Date accepted 16 May 1996 107
108
MEDICAL HYPOTHESES
in 1956 by Stoughton and Novak (9), who demon- ference by antigen modification, caused by the drug strated the disruption of tonofibrils and so-called and possibly eliciting autoantibody production (1). 'intercellular bridges' by disulfide-splitting agents The fact that several reported cases of drug-induced such as cysteine and reduced glutathione. This ob- pemphigus did not show tissue-bound or circulating servation was made long before the first report of intercellular antibodies, whereas others did (12,13), drug-induced pemphigus by Degos et al in 1969 (10). indicates that the two above-mentioned mechanisms The striking structural similarities between cysteine (a and b) might play a role in the development of the and penicillamine, together with the fact that the latter disease, either together or individually. may induce pemphigus, led to the speculation that it It is noteworthy that the primary step of drugmay cause acantholysis as well. Indeed, Ruocco et al induced acantholysis is the same for these two (3) demonstrated that the addition of D-penicillamine mechanisms and it is this biochemical step that we to normal human skin specimens caused acantholytic will address and offer a modification to the tradisplitting (biochemical acantholysis) very similar to tional and well-established concept of what are the that produced by pemphigus serum (immunologic dynamics of the disease process. acantholysis). The first step in drug-induced acantholysis (bioFurther experiments were then carried out by chemical and/or immunological) involves binding of different teams (1-8) to verify the in vitro acan- the drug to the cell membrane and the formation tholytic property of both natural (cysteine, reduced of 'drug--cysteine' instead of 'cysteine-cysteine' glutathione) and medicamentous thiols, such as bondings (Fig., Reaction 1). These newly formed penicillamine, captopril, thiopronine and piroxicam, anomalous disulfides are inadequate to the normal and recently, nutritional factors (11). cell-cell adhesion (based on cystine disulfide bonds), Those experiments revealed that, in addition to thus resulting in dyshesion between keratinocytes that the specific type of thiol added to the specimen, its subsequently leads to acantholysis with no immune concentration and time of action, the intensity of mediation. Alternatively, the anomalous disulfides in vitro acantholysis also depends upon the indivi- may lead to a change in the conformation of these dual susceptibility of the skin-donor. Moreover, they cell-surface antigens, rendering them immunogenic proved that thiol drugs are able to provoke acantho- with a resultant autoantibody formation (reviewed lysis without antibody mediation, a phenomenon that in Ref. 1). has been termed 'biochemical acantholysis', and that, Today, it is generally accepted that the primary again, susceptibility to the acantholytic effect of drugs target of D-penicillamine action is the cystine varies from person to person (4,11). disulfide bonds leading to the formation of cysteineOn the whole, a variety of heterogenous factors, penicillamine mixed disulfides (Fig., Reaction 1). such as inherited gene disorders (Hailey-Hailey), This chemical reaction is probably responsible for the intercellular antibodies (idiopathic pemphigus), and drug's action and also for its side-effects (1,14-18). drugs (mainly thiol drugs) may all interfere with cell-cell adhesion, resulting in acantholysis. As to pemphigus, it is generally accepted that the onset A proposed addition to the established reaction: and, above all, the progress of the disease depends the initiation of a chain reaction on a variable interaction of endogenous (genetic and autoimmune) and exogenous (inducing) factors. We suggest that the reaction of D-penicillamine Genetic predisposition alone ('the soil') is certainly with cystine disulfides that results in cysteineessential, although not in itself sufficient for causing penicillamine disulfides is not a terminal reaction, an outbreak of pemphigus; the intervention of exo- but rather a primary initiating step of a chain reaction. genous, heterogenous factors ('the seed') often appears It is reasonable to consider that the cysteineto be no less decisive in triggering and activating the penicillarnine disulfide is continuing to be enzymatifull-blown disease. cally reduced by various thiol reductants, in particular glutathione reductase, thereby generating a 'new' penicillamine molecule which, in turn, reacts with Pathogenic hypotheses on thiol-induced other cystine disulfides and does so in an unending acantholysis cycle (19) (Fig., Reaction 2). A chain reaction is thus created, in which the drug is repeatedly generated Although the mechanisms involved in drug-induced so that one molecule of the drug may attack thousands acantholysis are not well understood, two hypotheses of cystine disulfide bonds. This reaction may continue have been proposed: (a) direct biochemical drug uninterruptedly until it is interfered with by other interference with keratogenesis; and (b) indirect inter- external factors. It is highly probable that normal
109
PATHOMECHANISMS OF THIOL-INDUCED ACANTHOLYSIS
Reaction 1
KS-SK
+
P-SH
-~ K S - S - P
+
K-SH
Reaction 2
KS-S-P
Fig.
Reductase
K-SH
+ P-SH KS-SK
= cysteine disulfide b o n d
P-SH
= penicillamine
Possible biochemical reactions in thiol-induced acantholysis.
individuals have their own endogenous means of controlling this deleterious chain reaction, whereas pemphigus-prone individuals lack the ability to stop this potentially damaging reaction. There are many other examples of genetic differences in drug-metabolizing enzymes that are associated with adverse drug-reactions in susceptible individuals (20). Well-known examples of adverse drug-reactions related to pharmacogenetic disorders in drug metabolism are: (1) Procainamide- and hydralazine-induced lupus erythematosus related to slow acetylation (21); (2) sulphonamide- and anticonvulsant-induced hypersensitivity syndromes, probably associated with a defect in the detoxification of oxidative metabolites of the drug (22,23); and (3) perhaps the best-known and classic example is glucose-6-phosphate dehydrogenase deficiency and susceptibility of the red blood cells to oxidizing drugs. We believe that such a chain reaction may effectively explain the high reactivity of the thiol drugs and their ability to cause extensive acantholysis even at low concentrations. We recognize that it would be overly simplistic to assume that the reactions described above are the only ones involved in this process. The actual molecular and biochemical events are more likely to be manifold and complex, and the myriad of combined, additive, synergistic and antagonistic effects are boundless. It is our conviction, however, that we have gained some more insight into the basic biochemical reactions involved in this disease process. It is our hope that, with the recent advances in molecular biology, it will be possible in the future to phenotype people who are
unable to control the deleterious chain reaction outlined here. Preventing these susceptible individuals from exposure to certain drugs, such as penicillamine, might then prevent the appearance of the disease. References 1. Ruocco V, de Angelis E, Lombardi M L. Drug-induced pemphigus. II. Pathomechanisms and experimental investigations. Clin Dermatol 1993; 11: 507-513. 2. Ruocco V. L'acantolisi in vivo ed in vitro. Ann Ital Dermatol Clin Sper 1993; 47: 29--40. 3. Ruocco V, de Luca M, Pisani M et al. Pemphigus provoked by D-penicillamine. An experimental approach using in vitro tissue cultures. Dermatologica 1982; 164: 236-248. 4. Ruocco V, de Angelis E, Lombardi M L. In vitro acantholysis by captopril and thiopronine. Dermatologica 1988; 176: 115-123. 5. Yokel B K, Hood A F, Anhalt G J. Induction of acantholysis in organ explant culture by penicillamine and captopril. Arch Dermatol 1989; 125: 1367-1370. 6. Ruocco V, Pisani M, de Angelis E et al. Biochemical acantholysis provoked by thiol drugs. Arch Dermatol 1990; 126: 965-966. 7. De Dobbeleer G, Godfrine S, Gourdain J M e t al. In vitro acantholysis induced by D-penicillamine, captopril and piroxicam on dead de-epidermized dermis. J Cutan Pathol 1992; 19: 181-186. 8. Hashimoto K, Singer K, Lazarus G S. Penicillamine-induced pemphigus. Arch Dermatol 1984; 120: 762-766. 9. Stoughton R B, Novak N. Disruption of tonofibrils and intercellular bridges by disulfide-splitting agents. J Invest Dermatol 1956; 26: 127-136. 10. Degos T, Touraine R, Blaich S, Revuz J. Pemphigus chez un malade trait6 par penicillamine pour maladie de Wilson. Bull Soc Fr Dermatol Syphilogr 1969; 76:751-753. 11. Brenner S, Ruocco V, Wolf R, De Angelis E, Lombardi M L. Pemphigus and dietary factors. In vitro acantholysis by allyl
110
12. 13. 14.
15.
16. 17.
MEDICAL HYPOTHESES
compounds of the genus Allium. Dermatology 1995; 190: 197-202. Wolf R, Tamir A, Brenner S. Drug-induced versus drugtriggered pemphigus. Dermatologica 1991; 182:207-210. Wolf R, Brenner S. Arzeneimittelbedingter Pemphigus. Ubersicht. Z Hautkr 1990; 66: 289-293. Howard-Lock H E, Lock C J L, Mewa A, Kean W F. Dpenicillamine: chemistry and clinical use in rheumatic disease. Sem Arthr Rheum 1986; 15: 261-281. Yu T F, Roboz J, Johnson S, Kaung C. Studies on the metabolism of D-penicillamine and its interaction with probenecid in cystinuria and rheumatoid arthritis. J Rheumatol 1984; 11: 467-470. Huck F, de Medicis R, Lussier A, Dupuis G, Federlin P. Reducing property of some slow acting antirheumatic drugs. J Rheumatol 1984; 11: 605~09. Korman N J, Eyre R W, Zone J, Stanley J R. Drug-induced pemphigus: autoantibodies directed against the pemphigus antigen complexes are present in penicillamine and captopril-
induced pemphigus. J Invest Dermatol 1991; 96: 273-276. 18. Ruocco V, Pisani M. Induced pemphigus. Arch Dermatol Res 1982; 274: 123-140. 19. Drummer O H, Routley L, Christophidis N. Reversibility of disulfide formation. Comparison of chemical and enzymemediated reduction of penicillamine and captopril disulfides. Biochem Pharmacol 1987; 36:1197-1201. 20. Shear N H, Bhimji S. Pharmacogenetics and cutaneous reactions. Sem Dermatol 1989; 8: 219-226. 21. Breathnach S M, Hinter H. Lupus erythematosus (LE)-like syndrome induced by drugs. In: Breathnach S M, Hinter H, eds. Adverse Drug Reactions and the Skin. Oxford: Blackwell Scientific, 1992:113-118. 22. Shear N H, Speilberg S P, Grant D M e t al. Differences in metabolism of sulfonamides predisposing to idiosyncratic toxicity. Ann Intern Med 1986; 105: 179-184. 23. Shear N H, Speilberg S P. Anticonvulsant hypersensitivity syndrome. In vitro assessment of risk. J Clin Invest 1988; 82: 1826-1832.