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Drug Metabolism and Disposition Fast Forward
First published on June 6, 2007; DOI: 10.1124/dmd.107.015560

0090-9556/07/3509-1463-1465$20.00
DMD 35:1463-1465, 2007

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SHORT COMMUNICATION

Detection of Haptenated Proteins in Organotypic Human Skin Explant Cultures Exposed to Dapsone

Sanjoy Roychowdhury, Albert E. Cram, Al Aly, and Craig K. Svensson

Division of Pharmaceutics, College of Pharmacy, The University of Iowa, Iowa City, Iowa (S.R., C.K.S.); Department of Plastic Surgery, Mercy Hospital, Iowa City, Iowa (A.E.C., A.A.); and Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy & Pharmaceutical Sciences, Purdue University, West Lafayette, Indiana (C.K.S.)

Bioactivation of parent drug to reactive metabolite(s) followed by protein haptenation has been suggested to be a critical step in the elicitation of cutaneous drug reactions. Although liver is believed to be the primary organ of drug bioactivation quantitatively, other organs including skin may also metabolize drugs. Cultured human epidermal keratinocytes and dermal fibroblasts have been shown to be capable of bioactivating sulfonamides and sulfones, giving rise to haptenated proteins. It is, however, unclear whether metabolic events in these isolated cells reflect bioactivation in vivo. Hence, split-thickness human skin explants were exposed to dapsone (DDS) or its arylhydroxylamine metabolite (dapsone hydroxylamine, D-NOH) and probed for protein haptenation. DDS and D-NOH were applied either epicutaneously or mixed in the medium (to mimic its entry into skin from the systemic circulation). DDS-protein adducts were readily detected in skin explants exposed to either DDS or D-NOH. Adducts were detected mainly in the upper epidermal region in response to epicutaneous application, whereas adducts were formed all over the explants when DDS/D-NOH were mixed in the culture medium. In addition, adducts were visible in HLA-DR+ cells, indicating their presence in the dendritic cell population in the skin. Our results demonstrate the ability of intact human skin to bioactivate DDS leading to protein haptenation.

Address correspondence to: Dr. Craig K. Svensson, Office of the Dean, College of Pharmacy, Nursing and Health Sciences, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 49707. E-mail: svensson{at}purdue.edu




This article has been cited by other articles:


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C. K. Svensson
Biotransformation of Drugs in Human Skin
Drug Metab. Dispos., February 1, 2009; 37(2): 247 - 253.
[Abstract] [Full Text] [PDF]


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