Chlorpromazine, a candidate drug for photopheresis.
Photopheresis is a therapy for several T-cell-mediated disorders, aiming at a specific immune response against the pathogenic clone of T cells involved. With photopheresis, a mixture of patients' buffy coat and plasma, which contains 8-methoxypsoralen (8-MOP), is diluted with saline and exposed to ultraviolet A radiation (UVA). After the irradiation the treated fraction is reinfused. To improve this therapy and to broaden its scope, insight into the underlying mechanism is essential. Regarding the mechanism, photomodification of biomacromolecules is considered to be crucial in photopheresis. Up to the present, much emphasis has been put on the photobinding to DNA. However, photobinding to proteins can also play an important role in photopheresis, because much of the communication between the various parts of the immune system occurs via protein-protein interactions. In this study we compared the activity of 8-MOP and chlorpromazine (CPZ) in our animal model for photopheresis based on contact hypersensitivity. It proved that CPZ was able to induce specific immune suppression, just as 8-MOP. In addition, photobinding of CPZ and 8-MOP to lymphocytes was determined. It was shown that under conditions relevant for photopheresis the photobinding to DNA of 8-MOP exceeds that of CPZ by a factor of 22. This holds for both rat and human lymphocytes. With the photobinding to proteins it is just the other way round; the photobinding of CPZ exceeded that of 8-MOP by a factor of 23 for rat lymphocytes and 28 for human lymphocytes. This study proves that CPZ is an interesting candidate drug for photopheresis and shows that not only photobinding to DNA is crucial in photopheresis, but photobinding to proteins is important as well.
van Iperen
H P
HP
Department of Medicinal Photochemistry, Leiden/Amsterdam Center for Drug Research, Netherlands.
Beijersbergen van Henegouwen
M J
MJ
D019264:Adoptive Transfer; D000818:Animals; D002478:Cells, Cultured; D002746:Chlorpromazine / Q000627:therapeutic use*; D004247:DNA / Q000378:metabolism; D003877:Dermatitis, Contact / Q000188:drug therapy* / Q000276:immunology; D004139:Dinitrofluorobenzene / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology / Q000528:radiation effects; D008297:Male; D008730:Methoxsalen / Q000627:therapeutic use; D017893:Photopheresis; D017319:Photosensitizing Agents / Q000627:therapeutic use; D010853:Picryl Chloride / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000166:cytology / Q000276:immunology
D007166:Immunosuppressive Agents; D017319:Photosensitizing Agents; D011506:Proteins; D004247:DNA; D004139:Dinitrofluorobenzene; D002746:Chlorpromazine; D008730:Methoxsalen; D010853:Picryl Chloride