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Location of Ah receptor for dioxin
Correspondence Collagen concentration in Zyderm To the Editor: In their otherwise fine article "Zyderm Collagen: Implantation Technics (J AM ACAD DERMATOL 10: 273-278, 1984) Drs. Tromovitch, Stegman, and Glogau repeat an error that I have noted in the past from other sources. A little simple arithmetic shows that a concentration of 35 mg/ml is equal to 3.5%, and similarly 65 mg/ml equals 6.5%, not the 35% and 65% quoted. These figures of 35% and 65% have been repeated to me on several occasions by representatives of the manufacturer, and I suspect that the authors have had the same experience and have simply passed the figures on without checking. C. M. Leneck, M.D., F.R.C.P.(C) 4430 Bathurst St., Suite 511 Downsview, Ontario M3H 3S3, Canada
To the Editor: Dr. Leneck is indeed correct regarding the percent of collagen in Zyderm Implant. Drs. Tromovitch, Stegman, and Glogau, however, are not referring to the percent composition of collagen but to the percent volume persistence of Zyderm Implant following implantation. Zyderm Implant is produced in a dilute form so that it can be injected through a 30-gauge needle. Following injection into the dermis much of the saline is absorbed by the dermis until the resulting collagen suspension reaches a stable concentration. The final volume for ZCI I is 25% to 35% of the original (injected volume) and for ZCI II, 50% to 65%. Because these figures resemble the 35 and 65 mg/ml concentration figures for the two products, mistakes of the sort quoted by Dr. Leneck are often made. Bruce B. Pharriss, Ph.D., Vice President Scientific Affairs, Collagen Corporation 2500 Faher Pl., PaIo Alto, CA 94303
Replies To the Editor: Dr, Leneck is correct. Zyderm I (35 mg/ml) is 3.5% by dly weight and Zyderrn II (65 mg/ml) is 6.5% by dly weight. We appreciate Dr. Leneck for bringing this to the attention of the readers: However, the origin of the error is understandable. The amount of dry weight collagen in the syringes is either 3.5% or 6.5%, but after expansion with fluid, the collagen approximates one-third and two-thirds volume to remain in the tissue after absorption of the saline and lidocaine diluent. This absorption of the diluent necessitates the technic of overcorrecting depressions with Zyderm by injecting sufficient material to raise the contour above the desired level. In addition, the absorption of the diluent protects from permanent overcorrection and adds to the margin of safety seen with Zyderm. The Collagen Corporation has never implied concentrations of 35% and 65% but has carefully stated that the net volume of the products was approximately 35% and 65%. Their representatives in the field may have inadvertently repeated our error, but the official publications of the company have been more diligent. Samuel J. Stegman, M.D., Theodore A. Tromovitch, M.D., and Richard G. Glogau, M.D. 350 Parnassus Ave., San Francisco, CA 94117
Location of Ah receptor for dioxin To the Editor: We thoroughly enjoyed Dr, William Dunagin's review of dioxin toxicity (J AM ACAD DER~TOL 10:688-700, 1984). He managed to assemble scattered pieces of information from diverse literature into a coherent article that will surely become a standard reference in dermatology. However, we would like to point out that the cellular receptor that appears to mediate the toxicity of dioxins (Ah-A romatic hydrocarbon receptor, referred to on page 690) does not reside in the ,cell membrane," The receptor for tetrachlorodibenzo-pdioxin (TCDD) and related compounds is a soluble intracellular protein. In most structural and functional characteristics the Ah receptor appears to be closely related to receptors that bind various classes of steroid honnonesJ (No known steroids bind to the Ah receptor, however.) Until recently the standard model of A h receptor function and steroid hormone function represented these receptors as residing in the cytoplasm prior to binding to their respective ligands. 1'2 When occupied by their specific ligands in intact cells, these ligand-receptor complexes strongly associate with specific chromatin sites within the nucleus, thereby regulating genes that control specific biologic responses. Although the ultimate action within the nucleus is generally agreed 663
Journal of the American Academy of Dermatology
Correspondence
664
upon, there now is controversy as to the initial intracellular location o f " u n o c c u p i e d " forms o f the Ah receptor 3 and steroid h o r m o n e receptors. 4'5 Some evidence has been obtained suggesting that these receptors, prior to ligand binding, may be predominantly in the nucleus rather than in the cytoplasm. The outcome of this debate will depend on continuing research; nevertheless, the Ah receptor has been shown n o t to be membrane in origin.
Neil H. Shear, M.D., and Allan B. Okey, Ph.D. Hospital for Sick Children, University of Toronto 555 University Ave., Toronto, Ontario Canada M5G 1X8 REFERENCES 1. Eisen HJ, Hannah RR, Legraverend C, et al: The Ah receptor: Controlling factor in the induction of drugmetabolizing enzymes by certain chemical carcinogens and other environmental pollutants, in Litwack G, editor: Biochemical actions of hormones. New York, 1983, Academic Press Inc., vol. 10, pp. 227-257. 2. Jensen EV, DeSombre E: Estrogen-receptor interaction. Science 182:126-1134, 1973. 3. Whitlock JP, Galeazzi DR: 2,3,7,8-Tetrachlorodibenzop-dioxin receptors in wild type and variant mouse hepatoma eells: Nuclear location and strength of nuclear binding. J Biol Chem 259:980-985, 1984. 4. King WJ, Greene GL: Monoclonal antibodies localize oestrogen receptor in the nuclei of target cells. Nature 307:745-747, 1984. 5. Welshons WV, Lieberman ME, Gorski J: Nuclear localization of unoccupied oestrogen receptors. Nature 307: 747-749, 1984.
fects occur at concentrations of T C D D lower than those for any of the enzyme changes modulated by the Ah receptor. Both mechanisms are probably involved in dioxin toxicity. However, this will remain an important area for further basic science research until the issue is more clearly understood.
William G. Dunagin, M.D. Division of Dermatology, University of Missouri-Columbia M173 Medical Center, Columbia, 340 65212 REFERENCES 1. Okey AB, Bondy GP, Mason ME, et al: Temperaturedependent cytosol-to-nucleus translocation of the Ah receptor for 2,3,7,8-tetraehlorodibenzo-p-dioxin in continuous cell culture lines. J Biol Chem 255:11415-11422, 1980. 2. Okey AB, Bondy GP, Mason ME, et al: Regulatory gene product of the Ah locus. Characterization of the cytosolic inducer-receptor complex and evidence for its nuclear translocation. J Biol Chem 254:11636-11648, 1979. 3. Poland A, Knutson J, Glover E: A consideration of the mechanism of action of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons, in Tucker RE, et al, editors: Human and environmental risks of chlorinated dioxins and related compounds. New York, 1983, Plenum Press, pp. 539-559. 4. Brewster DW, Madhukar BV, Matsumura F: Influence of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the proteincomposition of the plasma membrane of hepatic cells from the rat. Biochem Biophys Res Commun 107: 68-74, 1982. 5. Matsumura F: Biochemical aspects of action mechanisms of 2, 3,7,8-tetrachlorodibenzo-p-dioxin and related chemicals in animals. Pharmacol Ther 19:195-209, 1982.
Reply To the Editor: Drs. Shear and Okey are correct in pointing out that the Ah receptor is intracellular. Dr. O k e y ' s group has made several important contributions to understanding this receptor and its actions, t,'-' The Ah receptor is very important in controlling microsomal mono-oxygenase and several coordinately expressed enzymes. There m a y also be other mechanisms for tetrachlorodibenzop-dioxin (TCDD) toxicity. F o r example, many cell types have the Ah receptor, but only some develop T C D D t o x i c i t y ? Many compounds are known to induce microsomal enzymes but are not nearly as toxic as TCDD. 4 Alterations of the cell membrane not attributable to the Ah receptor have been documented. 4,5 Recently, Matsumura* presented evidence that cell membrane ef*Matsumura F: Alteration of cell membrane function, causing widespread metabolic changes. Symposium on Public Health Risks of the Dioxins, Rockefeller University, Oct. 19-20, 1983.
Measurement of cure rate in onychomycosis To the Editor: I enjoyed the article by Zaias and Drachman concerning a method for determining the cure rate in treatment of fungal infection of nails (J AM ACAO DER~aAroe 9:912-919, 1983). However, I was surprised to read of the use of the proximal nail fold as one parameter of linear measurement; to me, it would seem that this line would vary from time to time, depending on the degree of manicuring, etc. Some years ago I wrote of my experience in onycholysis, in which measurement was taken from the distal edge of the lunula to the proximal point of pathologic nail involvement? In my experience, this provides a more stable point for longitudinal measurement and it appeared to be an area that remained fixed
To the Editor: Dr. Leneck is indeed correct regarding the percent of collagen in Zyderm Implant. Drs. Tromovitch, Stegman, and Glogau, however, are not referring to the percent composition of collagen but to the percent volume persistence of Zyderm Implant following implantation. Zyderm Implant is produced in a dilute form so that it can be injected through a 30-gauge needle. Following injection into the dermis much of the saline is absorbed by the dermis until the resulting collagen suspension reaches a stable concentration. The final volume for ZCI I is 25% to 35% of the original (injected volume) and for ZCI II, 50% to 65%. Because these figures resemble the 35 and 65 mg/ml concentration figures for the two products, mistakes of the sort quoted by Dr. Leneck are often made. Bruce B. Pharriss, Ph.D., Vice President Scientific Affairs, Collagen Corporation 2500 Faher Pl., PaIo Alto, CA 94303
Replies To the Editor: Dr, Leneck is correct. Zyderm I (35 mg/ml) is 3.5% by dly weight and Zyderrn II (65 mg/ml) is 6.5% by dly weight. We appreciate Dr. Leneck for bringing this to the attention of the readers: However, the origin of the error is understandable. The amount of dry weight collagen in the syringes is either 3.5% or 6.5%, but after expansion with fluid, the collagen approximates one-third and two-thirds volume to remain in the tissue after absorption of the saline and lidocaine diluent. This absorption of the diluent necessitates the technic of overcorrecting depressions with Zyderm by injecting sufficient material to raise the contour above the desired level. In addition, the absorption of the diluent protects from permanent overcorrection and adds to the margin of safety seen with Zyderm. The Collagen Corporation has never implied concentrations of 35% and 65% but has carefully stated that the net volume of the products was approximately 35% and 65%. Their representatives in the field may have inadvertently repeated our error, but the official publications of the company have been more diligent. Samuel J. Stegman, M.D., Theodore A. Tromovitch, M.D., and Richard G. Glogau, M.D. 350 Parnassus Ave., San Francisco, CA 94117
Location of Ah receptor for dioxin To the Editor: We thoroughly enjoyed Dr, William Dunagin's review of dioxin toxicity (J AM ACAD DER~TOL 10:688-700, 1984). He managed to assemble scattered pieces of information from diverse literature into a coherent article that will surely become a standard reference in dermatology. However, we would like to point out that the cellular receptor that appears to mediate the toxicity of dioxins (Ah-A romatic hydrocarbon receptor, referred to on page 690) does not reside in the ,cell membrane," The receptor for tetrachlorodibenzo-pdioxin (TCDD) and related compounds is a soluble intracellular protein. In most structural and functional characteristics the Ah receptor appears to be closely related to receptors that bind various classes of steroid honnonesJ (No known steroids bind to the Ah receptor, however.) Until recently the standard model of A h receptor function and steroid hormone function represented these receptors as residing in the cytoplasm prior to binding to their respective ligands. 1'2 When occupied by their specific ligands in intact cells, these ligand-receptor complexes strongly associate with specific chromatin sites within the nucleus, thereby regulating genes that control specific biologic responses. Although the ultimate action within the nucleus is generally agreed 663
Journal of the American Academy of Dermatology
Correspondence
664
upon, there now is controversy as to the initial intracellular location o f " u n o c c u p i e d " forms o f the Ah receptor 3 and steroid h o r m o n e receptors. 4'5 Some evidence has been obtained suggesting that these receptors, prior to ligand binding, may be predominantly in the nucleus rather than in the cytoplasm. The outcome of this debate will depend on continuing research; nevertheless, the Ah receptor has been shown n o t to be membrane in origin.
Neil H. Shear, M.D., and Allan B. Okey, Ph.D. Hospital for Sick Children, University of Toronto 555 University Ave., Toronto, Ontario Canada M5G 1X8 REFERENCES 1. Eisen HJ, Hannah RR, Legraverend C, et al: The Ah receptor: Controlling factor in the induction of drugmetabolizing enzymes by certain chemical carcinogens and other environmental pollutants, in Litwack G, editor: Biochemical actions of hormones. New York, 1983, Academic Press Inc., vol. 10, pp. 227-257. 2. Jensen EV, DeSombre E: Estrogen-receptor interaction. Science 182:126-1134, 1973. 3. Whitlock JP, Galeazzi DR: 2,3,7,8-Tetrachlorodibenzop-dioxin receptors in wild type and variant mouse hepatoma eells: Nuclear location and strength of nuclear binding. J Biol Chem 259:980-985, 1984. 4. King WJ, Greene GL: Monoclonal antibodies localize oestrogen receptor in the nuclei of target cells. Nature 307:745-747, 1984. 5. Welshons WV, Lieberman ME, Gorski J: Nuclear localization of unoccupied oestrogen receptors. Nature 307: 747-749, 1984.
fects occur at concentrations of T C D D lower than those for any of the enzyme changes modulated by the Ah receptor. Both mechanisms are probably involved in dioxin toxicity. However, this will remain an important area for further basic science research until the issue is more clearly understood.
William G. Dunagin, M.D. Division of Dermatology, University of Missouri-Columbia M173 Medical Center, Columbia, 340 65212 REFERENCES 1. Okey AB, Bondy GP, Mason ME, et al: Temperaturedependent cytosol-to-nucleus translocation of the Ah receptor for 2,3,7,8-tetraehlorodibenzo-p-dioxin in continuous cell culture lines. J Biol Chem 255:11415-11422, 1980. 2. Okey AB, Bondy GP, Mason ME, et al: Regulatory gene product of the Ah locus. Characterization of the cytosolic inducer-receptor complex and evidence for its nuclear translocation. J Biol Chem 254:11636-11648, 1979. 3. Poland A, Knutson J, Glover E: A consideration of the mechanism of action of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons, in Tucker RE, et al, editors: Human and environmental risks of chlorinated dioxins and related compounds. New York, 1983, Plenum Press, pp. 539-559. 4. Brewster DW, Madhukar BV, Matsumura F: Influence of 2,3,7,8-tetrachlorodibenzo-p-dioxin on the proteincomposition of the plasma membrane of hepatic cells from the rat. Biochem Biophys Res Commun 107: 68-74, 1982. 5. Matsumura F: Biochemical aspects of action mechanisms of 2, 3,7,8-tetrachlorodibenzo-p-dioxin and related chemicals in animals. Pharmacol Ther 19:195-209, 1982.
Reply To the Editor: Drs. Shear and Okey are correct in pointing out that the Ah receptor is intracellular. Dr. O k e y ' s group has made several important contributions to understanding this receptor and its actions, t,'-' The Ah receptor is very important in controlling microsomal mono-oxygenase and several coordinately expressed enzymes. There m a y also be other mechanisms for tetrachlorodibenzop-dioxin (TCDD) toxicity. F o r example, many cell types have the Ah receptor, but only some develop T C D D t o x i c i t y ? Many compounds are known to induce microsomal enzymes but are not nearly as toxic as TCDD. 4 Alterations of the cell membrane not attributable to the Ah receptor have been documented. 4,5 Recently, Matsumura* presented evidence that cell membrane ef*Matsumura F: Alteration of cell membrane function, causing widespread metabolic changes. Symposium on Public Health Risks of the Dioxins, Rockefeller University, Oct. 19-20, 1983.
Measurement of cure rate in onychomycosis To the Editor: I enjoyed the article by Zaias and Drachman concerning a method for determining the cure rate in treatment of fungal infection of nails (J AM ACAO DER~aAroe 9:912-919, 1983). However, I was surprised to read of the use of the proximal nail fold as one parameter of linear measurement; to me, it would seem that this line would vary from time to time, depending on the degree of manicuring, etc. Some years ago I wrote of my experience in onycholysis, in which measurement was taken from the distal edge of the lunula to the proximal point of pathologic nail involvement? In my experience, this provides a more stable point for longitudinal measurement and it appeared to be an area that remained fixed