Abstract
Telaprevir used as a protease inhibitor against hepatitis C virus is frequently associated with cutaneous adverse reactions. To explore a histological biomarker of cutaneous adverse events induced by telaprevir, we systematically searched for genes that were dysregulated by telaprevir in normal human epidermal keratinocytes (NHEKs). Microarray analysis and real-time polymerase chain reaction (PCR) revealed the significant increase in the expression of S100 calcium-binding protein A2 (S100A2) gene following treatment of NHEKs with telaprevir. Immunohistochemical analysis demonstrated that the expression of S100A2 was dominant in the spinous layer of the epidermis in patients with telaprevir-mediated severe-type drug eruptions and limited to the basal layer of the epidermis in healthy subjects. Furthermore, S100A2 expression increased after treatment with trichloroethylene and other medications, and the degree of S100A2 expression correlated with the severity of cutaneous adverse events. S100A2 expression also significantly increased in the skin of patients with atopic dermatitis and psoriasis. Taken together, S100A2 is highly expressed in the epidermis under inflammatory conditions and drug eruptions and may serve as a marker for keratinocyte damage in response to any inflammatory or toxic condition.
Highlights
Telaprevir used as a protease inhibitor against hepatitis C virus is frequently associated with cutaneous adverse reactions
lymphocyte stimulation test (LST) was negative in all five tested individuals, no probable causative new drug other than telaprevir was administered to each patient just before the appearance of eruptions
We first demonstrate the upregulated expression of S100 calcium-binding protein A2 (S100A2) in keratinocytes of patients with drug eruption in response to telaprevir, which frequently causes severe drug eruptions
Summary
Telaprevir used as a protease inhibitor against hepatitis C virus is frequently associated with cutaneous adverse reactions. Microarray analysis and real-time polymerase chain reaction (PCR) revealed the significant increase in the expression of S100 calcium-binding protein A2 (S100A2) gene following treatment of NHEKs with telaprevir. S100A2 is highly expressed in the epidermis under inflammatory conditions and drug eruptions and may serve as a marker for keratinocyte damage in response to any inflammatory or toxic condition. There are some key mediators for disseminated keratinocyte death in Stevens–Johnson syndrome and toxic epidermal necrolysis[4], the clinical outcome of treatment for severe-type drug eruption remains unsatisfactory. Microarray analysis of keratinocytes after telaprevir treatment revealed that S100A2 expression increased in the epidermis of patients with drug eruptions. We found S100A2 overexpression in the epidermis of patients with other inflammatory skin diseases, suggesting the role of S100A2 as a marker of keratinocyte damage in response to any inflammatory and toxic condition
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