Mårs U, Larsson B S
Department of Pharmaceutical Biosciences, Biomedical Center, Uppsala University, Sweden.
Pigment Cell Res. 1999 Aug;12(4):266-74. doi: 10.1111/j.1600-0749.1999.tb00760.x.
Certain drugs and chemicals, such as chloroquine, chlorpromazine, and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), are bound to melanin and retained in pigment cells for long periods. This specific retention in pigmented tissues can cause adverse effects in the skin, eye, inner ear, and pigmented nerve cells of the substantia nigra of the brain. To date, all studies have been focused on eu- and neuromelanin. In the present study, we show that chloroquine, chlorpromazine, chlomipramine, paraquat, acridine orange, and nickel, which are bound to eumelanin, also bind to synthetic pheomelanin, but the binding to pheomelanin is lower. The binding varied with the cysteine content and pH, and the results indicate that the binding is complex and includes ionic interactions. In addition, we have shown that these substances also bind to synthetic thiourea-containing melanin, but to quite a low extent. We also present a microautoradiographic study on the binding of 14C-chloroquine to natural pheomelanin in vivo in yellow mice C57BL (Ay/a). Black (C57/BL) and albino (NMRI) mice were used as controls. The autoradiography demonstrated a pronounced uptake of chloroquine in the hair follicles and the dermal melanocytes in the ear of yellow mice, which was comparable to the corresponding accumulation of label in black mice. In the albino mouse, the uptake was lower and more homogeneously distributed in the skin. These results suggest that the toxicological risks of melanin-related adverse effects are applicable to persons with a high content of pheomelanin in the skin and hair.
某些药物和化学物质，如氯喹、氯丙嗪和1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP），会与黑色素结合并长期保留在色素细胞中。这种在色素组织中的特异性保留会对皮肤、眼睛、内耳以及大脑黑质中的色素神经细胞产生不良影响。迄今为止，所有研究都集中在真黑素和神经黑素上。在本研究中，我们发现与真黑素结合的氯喹、氯丙嗪、氯米帕明、百草枯、吖啶橙和镍，也能与合成的褐黑素结合，但与褐黑素的结合力较低。结合力随半胱氨酸含量和pH值而变化，结果表明这种结合是复杂的，包括离子相互作用。此外，我们还表明这些物质也能与合成的含硫脲黑色素结合，但程度相当低。我们还进行了一项微量放射自显影研究，观察了14C-氯喹在黄色C57BL（Ay/a）小鼠体内与天然褐黑素的结合情况。以黑色（C57/BL）和白化（NMRI）小鼠作为对照。放射自显影显示，氯喹在黄色小鼠耳部的毛囊和真皮黑素细胞中有明显摄取，这与黑色小鼠中相应的标记物积累情况相当。在白化小鼠中，摄取量较低，且在皮肤中分布更均匀。这些结果表明，与黑色素相关的不良反应的毒理学风险适用于皮肤和头发中褐黑素含量高的人群。
