Role for inner ring deiodination preventing transcutaneous passage of thyroxine
Abstract
Creams containing thyroid hormone are commonly employed for cosmetic purposes. To verify whether T(4) applied to the skin surface can enter the bloodstream either directly or as a metabolite, a cream containing L-T(4) [3,5,3',5'-tetraiodothyronine (T(4))] was self-applied by volunteers for 2 wk. No significant variations in urinary iodide, TSH, and serum (total and free) T(4) and T(3) concentrations were observed at any time relative to pretreatment values, whereas rT(3) concentrations increased significantly 6 and 12 h after cream application. The increased rT(3) concentration led us to investigate the presence of inner ring type III deiodinase (D3) activity in human skin. Using human surgical discard skin, we found that T(4) can be carried across human epidermis in a liposome cream. Substantial inner ring deiodination was suggested by the fact that only 10% of transferred thyroid hormone remained as T(4), and T(3) was not detected. We then measured D3 activity in a surgical skin specimen. The K(m) for T(3) was 1.74 nmol/liter, and the maximum velocity was 23.5 fmol/microg microsomal protein/h. In conclusion, our study indicates that normal human skin serves as a substantial, but incomplete, barrier to T(4) passage. D3 plays an important role in augmenting T(4) blockade by inactivating T(4) to rT(3).
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Only 10% of LT4 applied to bare skin was transferred through the epidermis, whereas a greater portion of LT4 was degraded by type III deiodinase in the skin.
“According to a previous study by Santini et al, only 10% of LT4 applied to bare skin was transferred through the epidermis, whereas a greater portion of LT4 was degraded by type III deiodinase in the skin (265).”
From Levothyroxine: conventional and novel drug delivery formulations. (2023) · cites this paper as [265]
Cites
Fitzpatrick’s Dermatology in General Medicine
(1999) · Heart & Lung · doi:10.1016/s0147-9563(99)70018-x · Cited by 3,234 · see citing works
Bianco, A. C., Salvatore, D., Gereben, B., Berry, M. J., & Larsen, P. R. (2002) · Endocrine Reviews · doi:10.1210/edrv.23.1.0455 · Cited by 1,853 · see citing works
Werner & Ingbar's the thyroid : a fundamental and clinical text
Werner, S. C., Ingbar, S. H., Braverman, L. E., & Utiger, R. D. (2012) · Lippincott-Raven eBooks · Cited by 1,016 · see citing works
Self-citationMaternal and Fetal Thyroid Function
Epstein, F. H., Burrow, G. N., Fisher, D. A., & Larsen, P. R. (1994) · New England Journal of Medicine · doi:10.1056/nejm199410203311608 · Cited by 720 · see citing works
Hennemann, G., Docter, R., Friesema, E. C. H., de Jong, M., Krenning, E. P., & Visser, T. J. (2001) · Endocrine Reviews · doi:10.1210/edrv.22.4.0435 · Cited by 394 · see citing works
Action of thyroid hormone in brain
Bernal, J. (2002) · Journal of Endocrinological Investigation · doi:10.1007/bf03344003 · Cited by 355 · see citing works
The Deiodinase Family of Selenoproteins
GERMAIN, D. L. S., & GALTON, V. A. (1997) · Thyroid · doi:10.1089/thy.1997.7.655 · Cited by 342 · see citing works
Expression Profiles of the Three Iodothyronine Deiodinases, D1, D2, and D3, in the Developing Rat1
Bates, J. M., Germain, D. L. S., & Galton, V. A. (1999) · Endocrinology · doi:10.1210/endo.140.2.6537 · Cited by 242 · see citing works
Physical and physiological effects of stratum corneum tape stripping
Bashir, S. J., Chew, A., Anigbogu, A., Dreher, F., & Maïbach, H. I. (2001) · Skin Research and Technology · doi:10.1034/j.1600-0846.2001.007001040.x · Cited by 213 · see citing works
Salvatore, D., Low, S. C., Berry, M. J., Maia, A. L., Harney, J. W., Croteau, W., Germain, D. L. S., & Larsen, P. R. (1995) · Journal of Clinical Investigation · doi:10.1172/jci118299 · Cited by 186 · see citing works
Becker, K. B., Stephens, K. C., Davey, J. C., Schneider, M. J., & Galton, V. A. (1997) · Endocrinology · doi:10.1210/endo.138.7.5272 · Cited by 185 · see citing works
Ontogeny of Iodothyronine Deiodinases in Human Liver1
Richard, K., Hume, R., Kaptein, E., Sanders, J. P., van Toor, H., de Herder, W. W., den Hollander, J. C., Krenning, E. P., & Visser, T. J. (1998) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.83.8.5032 · Cited by 147 · see citing works
Human Placenta Is an Active Site of Thyroxine and 3,3',5-Triiodothyronine Tyrosyl Ring Deiodination*
Roti, E., Fang, S. L., GREEN, K., Emerson, C. H., & Braverman, L. E. (1981) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-53-3-498 · Cited by 146 · see citing works
Self-citationCutaneous Metabolism of Xenobiotics
Kao, J., & Carver, M. P. (1990) · Drug Metabolism Reviews · doi:10.3109/03602539009041089 · Cited by 133 · see citing works
Santini, F., Chiovato, L., Ghirri, P., Lapi, P., Mammoli, C., Montanelli, L., Scartabelli, G., Ceccarini, G., Coccoli, L., CHOPRA, I. J., et al. (1999) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.84.2.5439 · Cited by 105 · see citing works
Self-citationSafer, J. D., Fraser, L. M., Ray, S., & Holick, M. F. (2001) · Thyroid · doi:10.1089/10507250152484547 · Cited by 100 · see citing works
Self-citationCampos‐Barros, Á., Hoell, T., Musa, A., Sampaolo, S., Stoltenburg, G., Pinna, G., Eravci, M., MEINHOLD, H., & Baumgartner, A. (1996) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.81.6.8964848 · Cited by 93 · see citing works
Thyroxine Inner Ring Monodeiodinating Activity in Fetal Tissues of the Rat
Huang, T., CHOPRA, I. J., Boado, R. J., Solomon, D. H., & TECO, G. N. C. (1988) · Pediatric Research · doi:10.1203/00006450-198802000-00014 · Cited by 61 · see citing works
Self-citationArcher, C. B. (2010) · Wiley eBooks · doi:10.1002/9781444317633.ch4 · Cited by 57 · see citing works
Pharmacokinetic implications of changing blood flow in skin
Riviere, J. E., & Williams, P. L. (1992) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600810628 · Cited by 42 · see citing works
Santini, F., CHOPRA, I. J., Hurd, R. E., Solomon, D. H., & TECO, G. N. C. (1992) · Endocrinology · doi:10.1210/endo.130.4.1547744 · Cited by 36 · see citing works
Self-citationSantini, F., Pinchera, A., Ceccarini, G., Castagna, M. G., Rosellini, V., Mammoli, C., Montanelli, L., Zucchi, V., CHOPRA, I. J., & Chiovato, L. (2001) · European Journal of Endocrinology · doi:10.1530/eje.0.1440577 · Cited by 33 · see citing works
Self-citationFleisher, D., Niemiec, S. M., Oh, C., Hu, Z., Ramachandran, C., & Weiner, N. (1995) · Life Sciences · doi:10.1016/0024-3205(95)02086-x · Cited by 28 · see citing works
Inner-ring deiodination of 3,5,3'-triiodothyronine in the in situ perfused guinea pig placenta.
Castro, M. I., Braverman, L. E., Alex, S., Wu, C. F., & Emerson, C. H. (1985) · Journal of Clinical Investigation · doi:10.1172/jci112188 · Cited by 26 · see citing works
Self-citationRapakax, R. S., Knight, P. W., & Prasad, V. K. (1981) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600700205 · Cited by 25 · see citing works
Roti, E., Fang, S.-L., Ch, E., & Braverman, L. E. (1981) · PubMed · Cited by 20 · see citing works
Self-citationVillar, D., Nicol, F., Arthur, J. R., DICKS, P., Cannavan, A., Kennedy, D. G., & Rhind, S. M. (2000) · Research in Veterinary Science · doi:10.1053/rvsc.1999.0344 · Cited by 19 · see citing works
Thyroid hormones in human tumoral and normal nervous tissues
Calvo, R. M., Roda, J. M., Obregón, M.-J., & de Escobar, G. M. (1998) · Brain Research · doi:10.1016/s0006-8993(98)00576-9 · Cited by 17 · see citing works
Methods for measuring iodine in urine and serum
RENDL, J., Bier, D. D., & Reiners, C. (2009) · Experimental and Clinical Endocrinology & Diabetes · doi:10.1055/s-0029-1212054 · Cited by 13 · see citing works
Evidence that the human placental 5-monodeiodinase is a phospholipid- requiring enzyme
Santini, F., CHOPRA, I. J., Solomon, D. H., & TECO, G. N. C. (1992) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.74.6.1592882 · Cited by 10 · see citing works
Self-citationGuerra, P. D., Caraccio, N., Simoncini, M., & Monzani, F. (1992) · International Archives of Occupational and Environmental Health · doi:10.1007/bf00386930 · Cited by 8 · see citing works
Flagged first, then by citations
1 of the 32 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Selenium, the Thyroid, and the Endocrine System
Köhrle, J., Jakob, F. J., Contempré, B., & Dumont, J. E. (2005) · Endocrine Reviews · doi:10.1210/er.2001-0034 · Cited by 527 · see citing works
Santini, F., Marzullo, P., Rotondi, M., Ceccarini, G., Pagano, L., Ippolito, S., Chiovato, L., & Biondi, B. (2014) · European Journal of Endocrinology · doi:10.1530/eje-14-0067 · Cited by 240 · see citing works
Self-citationLean Body Mass Is a Major Determinant of Levothyroxine Dosage in the Treatment of Thyroid Diseases
Santini, F., Pinchera, A., Marsili, A., Ceccarini, G., Castagna, M. G., Valeriano, R., Giannetti, M., Taddei, D., Centoni, R., Scartabelli, G., et al. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-1306 · Cited by 226 · see citing works
Self-citationDentice, M., Luongo, C., Huang, S. A., Ambrosio, R., Elefante, A., Mirebeau‐Prunier, D., Zavacki, A. M., Fenzi, G., Grachtchouk, M. A., Hutchin, M. E., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0706754104 · Cited by 176 · see citing works
Freitas, B. C. G., Gereben, B., Castillo, M., Kalló, I., Zeöld, A., Egri, P., Liposits, Z., Zavacki, A. M., Maciel, R. M. B., Jo, S., et al. (2010) · Journal of Clinical Investigation · doi:10.1172/jci41977 · Cited by 160 · see citing works
Physiological role and regulation of iodothyronine deiodinases: A 2011 update
Marsili, A., Zavacki, A. M., Harney, J. W., & Larsen, P. R. (2011) · Journal of Endocrinological Investigation · doi:10.1007/bf03347465 · Cited by 101 · see citing works
Topical Thyroid Hormone Accelerates Wound Healing in Mice
Safer, J. D., Crawford, T. M., & Holick, M. F. (2005) · Endocrinology · doi:10.1210/en.2005-0192 · Cited by 101 · see citing works
Self-citationReawakened interest in type III iodothyronine deiodinase in critical illness and injury
Huang, S. A., & Bianco, A. C. (2008) · Nature Clinical Practice Endocrinology & Metabolism · doi:10.1038/ncpendmet0727 · Cited by 95 · see citing works
Physiology and Pathophysiology of Type 3 Deiodinase in Humans
Huang, S. A. (2005) · Thyroid · doi:10.1089/thy.2005.15.875 · Cited by 92 · see citing works
Grozovsky, R., Ribich, S. A., Rosene, M. L., Mulcahey, M. A., Huang, S. A., Patti, M., Bianco, A. C., & Kim, B. W. (2008) · Endocrinology · doi:10.1210/en.2008-0938 · Cited by 72 · see citing works
Levothyroxine: conventional and novel drug delivery formulations.
Liu, H., Li, W., Zhang, W., Sun, S., & Chen, C. (2023) · Endocrine Reviews · doi:10.1210/endrev/bnac030 · Cited by 63 · see citing works
Smart polymeric nanofibers for topical delivery of levothyroxine
Fathi Azarbayjani, A., Venugopal, J. R., Ramakrishna, S., Lim, F. C., Chan, Y. W., & Chan, S. Y. (2010) · Journal of Pharmacy & Pharmaceutical Sciences · doi:10.18433/j3ts3g · Cited by 56 · see citing works
Di Donna, V., Santoro, M. G., de Waure, C., Ricciato, M. P., Paragliola, R. M., Pontecorvi, A., & Corsello, S. M. (2014) · Thyroid · doi:10.1089/thy.2014.0111 · Cited by 52 · see citing works
Thyroid hormone action on skin
Safer, J. D. (2012) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0b013e328357b45e · Cited by 51 · see citing works
Self-citationThyroid Hormone and Wound Healing
Safer, J. D. (2013) · Journal of Thyroid Research · doi:10.1155/2013/124538 · Cited by 43 · see citing works
Self-citationEffects of tyrosine kinase inhibitors on thyroid function and thyroid hormone metabolism
Basolo, A., Matrone, A., Elisei, R., & Santini, F. (2021) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2020.12.008 · Cited by 41 · see citing works
Self-citationAzarbayjani, A. F., Khu, J. V., Chan, Y. W., & Chan, S. Y. (2011) · Biopharmaceutics & Drug Disposition · doi:10.1002/bdd.766 · Cited by 24 · see citing works
Da Conceição, R. R., Fernandes, G. W., Fonseca, T. L., Bocco, B. M. L. C., & Bianco, A. C. (2018) · Thyroid · doi:10.1089/thy.2018.0205 · Cited by 23 · see citing works
Factitious Thyrotoxicosis Induced by Mesotherapy: A Case Report
Danilovic, D. L. S., BLOISE, W., Knobel, M., & Marui, S. (2008) · Thyroid · doi:10.1089/thy.2007.0233 · Cited by 22 · see citing works
Current concepts and challenges to unravel the role of iodothyronine deiodinases in human neoplasias
Goemann, I. M., Marczyk, V. R., Romitti, M., Wajner, S. M., & Maia, A. L. (2018) · Endocrine Related Cancer · doi:10.1530/erc-18-0097 · Cited by 20 · see citing works
The Thyroid Hormone Degrading Type 3 Deiodinase Is the Primary Deiodinase Active in Murine Epidermis
Huang, M. P., Rodgers, K. A., O'Mara, R., Mehta, M., Abu-Zahra, H., Tannenbaum, A. D., Persons, K. S., Holick, M. F., & Safer, J. D. (2011) · Thyroid · doi:10.1089/thy.2011.0105 · Cited by 18 · see citing works
Self-citationYazdanparast, P., Carlsson, B., Oikarinen, A., Risteli, J., & Faergemann, J. (2004) · Thyroid · doi:10.1089/105072504774193168 · Cited by 18 · see citing works
In vitro permeation of levothyroxine across the skin
Padula, C., Pappani, A., & Santi, P. (2007) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2007.08.004 · Cited by 17 · see citing works
Paus, R., Ramot, Y., Kirsner, R. S., & Tomic‐Canic, M. (2020) · Experimental Dermatology · doi:10.1111/exd.14156 · Cited by 15 · see citing works
A Thyroid Hormone Deiodinase Inhibitor Can Decrease Cutaneous Cell Proliferation In Vitro
Safer, J. D., Persons, K. S., & Holick, M. F. (2009) · Thyroid · doi:10.1089/thy.2008.0227 · Cited by 16 · see citing works
Self-citationThe Elemental Importance of Sufficient Iodine Intake: A Trace Is Not Enough
Visser, T. J. (2006) · Endocrinology · doi:10.1210/en.2006-0203 · Cited by 15 · see citing works
Goemann, I. M., Marczyk, V. R., Recamonde‐Mendoza, M., Wajner, S. M., Graudenz, M. S., & Maia, A. L. (2020) · Scientific Reports · doi:10.1038/s41598-020-70892-4 · Cited by 14 · see citing works
Tyrosine kinase inhibitor–induced hypothyroidism: mechanism and clinical implications
Wang, Z., Wang, H., Bu, C., Meng, B., Mu, Y., Gao, S., Chen, W., & Tao, X. (2024) · European Journal of Clinical Pharmacology · doi:10.1007/s00228-024-03626-4 · Cited by 9 · see citing works
The crosstalk between thyroid gland and adipose tissue: signal integration in health and disease
Santini, F., Marzullo, P., Rotondi, M., Ceccarini, G., Pagano, L., Ippolito, S., Chiovato, L., & Biondi, B. (2014) · Cited by 8 · see citing works
Self-citationAction of Topical Thyroid Hormone Analogues on Glucocorticoid-Induced Skin Atrophy in Mice
Yazdanparast, P., Carlsson, B., Sun, X.-Y., Zhao, X., Hedner, T., & Faergemann, J. (2006) · Thyroid · doi:10.1089/thy.2006.16.273 · Cited by 7 · see citing works
Kaykhaei, M. A., Shahraki, A. R., Mohammadi, M., Moshtaghian, B., & Zandkarimi, M. (2016) · Zahedan Journal of Research in Medical Sciences · doi:10.17795/zjrms-6449 · Cited by 4 · see citing works
Thyroid Hormone Ameliorates Lymphedema by Suppressing Adipogenesis in a Murine Lymphedema Model
Choi, J., Lee, K.-H., Kim, J., Jeong, W., Jo, T., Lee, H. W., Park, Y. S., & Park, S. W. (2022) · Lymphatic Research and Biology · doi:10.1089/lrb.2021.0079 · Cited by 1 · see citing works
Pera, D. T., Planello, J. F., Cancino‐Bernardi, J., Polikarpov, I., Zucolotto, V., de Avó, L. R. D. S., Germano, C. M. R., & Melo, D. G. (2014) · Journal of Nanotechnology in Engineering and Medicine · doi:10.1115/1.4028695
Gori, G., Negri, F. D., Fioravanti, A., Feo, F. D., Castiglioni, C., & Fini, E. (2025) · Future Pharmacology · doi:10.3390/futurepharmacol5030033
Luger, A., & Luger, T. A. (2006) · Springer eBooks · doi:10.1007/3-540-28782-5_22
Potential Therapeutic Uses of Thyroid Hormone
Safer, J. D., & Holick, M. F. (2008) · Springer eBooks · doi:10.1007/978-1-84800-187-9_14
Self-citation
- Authors
- Santini, F., Vitti, P., Chiovato, L., Ceccarini, G., Macchia, M., Montanelli, L., Gatti, G., Rosellini, V., Mammoli, C., Martino, E., Chopra, I. J., Safer, J. D., Braverman, L. E., & Pinchera, A.
- Affiliations
- University of Pisa (IT)
- University of Pavia (IT)
- University of California, Los Angeles (US)
- Boston University (US)
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2003-06
- Volume
- 88
- Issue
- 6
- Pages
- 2825-2830
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2106695259
- Cited by
- 37
- References
- 32
- Citations by year
- 2025: 1 · 2024: 1 · 2022: 2 · 2021: 1 · 2020: 2 · 2018: 2 · 2016: 2 · 2014: 4 · 2013: 1 · 2012: 1
- FWCI
- 1.61
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advancements in Transdermal Drug Delivery
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
- Keywords
- type III deiodinase, thyroxine, reverse T3, skin barrier, urinary iodide, thyroid-stimulating hormone, thyroid hormone metabolism
- MeSH terms
- Absorption, Adult, Female, Humans, Iodide Peroxidase, Iodine, Isoenzymes, Liposomes, Ointments, Skin, Thyroxine, Triiodothyronine
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
