ABSTRACT
We report two cases of bucillamine-induced bullous reactions with keratinocyte necrosis. The first patient, a 27-year-old woman, developed toxic epidermal necrolysis (TEN) over her whole body after taking bucillamine 300 mg/day for seven days. The second patient, a 63-year-old woman, developed several bullous erythemas on the mucous membranes and legs after taking bucillamine for more than two years. The fixed drug eruptions were diagnosed based on a provocation test in addition to clinical and histopathologic findings. These cases highlight the importance of considering fixed drug eruption as well as TEN in the differential diagnosis of bucillamine-induced bullous drug eruption.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Cysteine/analogs & derivatives , Drug Eruptions/etiology , Stevens-Johnson Syndrome/etiology , Stevens-Johnson Syndrome/pathology , Adult , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Arthritis, Rheumatoid/diagnosis , Arthritis, Rheumatoid/drug therapy , Biopsy, Needle , Cysteine/adverse effects , Cysteine/therapeutic use , Drug Eruptions/pathology , Female , Follow-Up Studies , Humans , Immunohistochemistry , Long-Term Care , Middle Aged , Risk Assessment , Severity of Illness IndexABSTRACT
A photosensitive form of trichothiodystrophy (TTD) results from mutations in the same XPD gene as the DNA-repair-deficient genetic disorder xeroderma pigmentosum group D (XP-D). Nevertheless, unlike XP, no increase in skin cancers appears in patients with TTD. Although the ability to repair ultraviolet (UV)-induced DNA damage has been examined to explain their cancer-free phenotype, the information accumulated to date is contradictory. In this study, we determined the repair kinetics of cyclobutane pyrimidine dimers (CPD) and (6-4)photoproducts (6-4PP) in three TTD cell strains using an enzyme-linked immunosorbent assay. We found that all three TTD cell strains are deficient in the repair of CPD and of 6-4PP. UV sensitivity correlated well with the severity of repair defects. Moreover, accumulation of repair proteins (XPB and proliferating cell nuclear antigen) at localized DNA damage sites, detected using micropore UV irradiation combined with fluorescent antibody labeling, reflected their DNA repair activity. Importantly, mutations of the XPD gene affected both the recruitment of the TFIIH complex to DNA damage sites and the TFIIH expression. Our results suggest that there is no major difference in the repair defect between TTD and XP-D and that the cancer-free phenotype in TTD is unrelated to a DNA repair defect.
Subject(s)
Fibroblasts/metabolism , Hair Diseases/metabolism , Hair Diseases/pathology , Pyrimidine Dimers/metabolism , DNA Helicases , DNA Repair , DNA-Binding Proteins/genetics , Fibroblasts/radiation effects , Hair Diseases/genetics , Humans , In Vitro Techniques , Microscopy, Fluorescence , Photochemistry , Severity of Illness Index , Skin/cytology , Xeroderma Pigmentosum/geneticsABSTRACT
We have recently developed a micropore ultraviolet irradiation technique. An isopore membrane filter with 3 microm diameter pores shields ultraviolet C radiation from cultured human fibroblasts, leading to partial irradiation within the cells with an average of about three exposed areas per nucleus. This study addressed the question of whether the spatial distribution of DNA damage within a cell nucleus is important in triggering ultraviolet-induced cytotoxicity. We have examined whether there are differences in cytotoxicity between partially ultraviolet-irradiated cells and uniformly irradiated cells after equal amounts of DNA damage were induced in the cell nuclei. We first determined DNA damage formation in normal human fibroblasts using an enzyme-linked immunosorbent assay. We found that 5 J per m2 ultraviolet irradiation produced an equivalent amount of cyclobutane pyrimidine dimers and (6-4) photoproducts per cell as 100 J per m2 with the membrane filter shield. At those doses, we found that both types of ultraviolet irradiation induced similar levels of cytotoxicity as assessed by a 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay. Both types of ultraviolet-irradiated cells also had similar cell-cycle distribution and apoptosis as measured by flow cytometry. Moreover, no significant differences in repair kinetics for either type of photolesion were observed between the two different ultraviolet treatments. Similar results were obtained in Cockayne syndrome cells that are defective in transcription-coupled nucleotide excision repair. Present results indicate that in the range of photoproducts studied, the spatial distribution of DNA damage within a cell is less important than the amount of damage in triggering ultraviolet-induced cytotoxicity.
