PHARMACOLOGICAL DISRUPTION OF HAIR FOLLICLE PIGMENTATION BY CYCLOPHOSPHAMIDE AS A MODEL FOR STUDYING THE MELANOCYTE RESPONSE TO AND RECOVERY FROM CYTOTOXIC DRUG DAMAGE IN-SITU

Here we show that cyclophosphamide induces disruption of follicular me lanogenesis, which is characterized by abnormal transfer of pigment gr anules to ectopic hair bulb locations, extrafollicular melanin inconti nence, disordered formation of melanosomes, and inhibition of melanoso me transfer into precortical keratinocytes. This is in contrast to dex amethasone-induced termination of follicle melanogenesis, which activa tes premature but predominantly normal catagen development. Cyclophosp hamide-induced pigmentation disruption was accompanied by significant alterations of biochemical and biophysical markers of melanogenesis, c ompared to control mice treated either with vehicle or with topical de xamethasone, Electron paramagnetic resonance spectroscopy shows a decl ine in the melanin signal and predominant eumelanin production, Tyrosi ne hydroxylase activity of tyrosinase and dihydroxyphenylalanine oxida tion drop rapidly, while DOPAchrome tautomerase activity increases and dihydroxyindole carboxylic acid conversion factor activity remains un changed in cyclophosphamide-treated mice compared to controls, These o bservations emphasize the key role of tyrosinase as opposed to postdih ydroxyphenylalanine oxidase steps in normal and pathological terminati on of melanogenesis and shows that tyrosinase is the most sensitive ta rget of the melanogenic apparatus for pharmacological regulation, Foll icle pigmentation recovers only during the subsequent hair cycle, i.e. , after a new anagen hair bulb has been constructed, which points to t he existence of a relatively chemoresistant melanoblast-like cell popu lation residing in the noncycling part of the hair follicle.