Strain-Dependent and Site-Specific Differences in Irinotecan-Induced Skin Pigmentation in Mice

Abstract

Skin pigmentation induced by irinotecan—an anticancer drug—is clinically recognized; however, strain-dependent and skin site-specific differences in its manifestation have not been sufficiently investigated in mice. In this study, we compared melanocyte activation in plantar and genital skin following repeated irinotecan administration in three mouse strains: ICR (Slc:ICR), C57BL/6 (C57BL/6JmsSlc), and C3H (C3H/HeSlc). Melanocyte activation was assessed by 3,4-dihydroxyphenylalanine (DOPA) staining and immunofluorescence staining for microphthalmia-associated transcription factor (MITF). Although no obvious macroscopic pigmentation was observed in any strain or skin site, DOPA staining revealed an increased number of DOPA-positive cells in the plantar skin of all three mouse strains. By contrast, marked strain-dependent differences were observed in the genital skin: DOPA-positive cells were detected in ICR (Slc:ICR) and C57BL/6 (C57BL/6JmsSlc) mice but not in C3H (C3H/HeSlc) mice. MITF immunofluorescence staining results were consistent with the DOPA staining findings, demonstrating enhanced MITF signals in skin sites exhibiting melanocyte activation. Notably, the induction of DOPA-positive cells in the genital skin of albino ICR mice was an unexpected finding, suggesting that drug-induced melanocyte activation may occur independently of intrinsic melanin-producing capacity and instead involve upstream regulatory pathways. Collectively, these findings demonstrate clear strain-dependent and skin site-specific differences in irinotecan-induced melanocyte responses and provide important insights into the heterogeneity of drug-induced skin pigmentation.