A phenolic amine compound, 4-S-cysteaminylphenol (4-S-CAP), was found to cause a selective destruction of follicular melanocytes. It was also recently found that 4-S-CAP can be a substrate for both tyrosinase and plasma monoamine oxidase (MAO). Both of these enzymes are capable of producing cytotoxic intermediates through their interaction with 4-S-CAP. To study the mechanism of selective melanocytotoxicity of phenolic amine compounds, we compared the in vivo depigmenting potency of 4-S-CAP and its three analogues; i.e., 4-S-HomoCAP, alpha-methyl(Me)-4-S-CAP and N,N-dimethyl(DiMe)-4-S-CAP, using black hair follicles. All four of these phenolic amine compounds possessed depigmenting potency. In this study we examined the kinetics of tyrosinase and MAO by these four compounds. 4-S-CAP and 4-S-HomoCAP were the substrates of both tyrosinase and MAO, whereas alpha-Me-4-S-CAP and N,N-DiMe-4-S-CAP were the substrates of tyrosinase alone. The rate of o-quinone formation by tyrosinase was not in parallel to the in vivo depigmenting potency of the tested compounds. It is therefore indicated that plasma MAO is not the enzyme directly responsible for the production of the melanocytotoxic intermediates from the phenolic amine compounds. We also found that the observed in vivo depigmentation results from complex processes involving the amount of o-quinone formed and the intracellular interaction of o-quinone with protein species.