De Marco Federico, Perluigi Marzia, Marcante Maria Luisa, Coccia Raffaella, Foppoli Cesira, Blarzino Carla, Rosei Maria Anna
Laboratory of Virology, Regina Elena Institute for Cancer Research, Via delle Messi d'Oro, 156-00156 Rome, Italy.
Biochem Pharmacol. 2002 Nov 15;64(10):1503-12. doi: 10.1016/s0006-2952(02)01353-9.
Tetrahydroisoquinolines (TIQs) are endogenous alkaloid compounds detected in urine, central nervous system and some peripheral tissues in Mammalia. No data are at present available on TIQ levels in skin, although in vitro biochemical evidences indicate that they may undergo auto-oxidation with production of reactive oxygen species or may be enzymatically converted into melanin pigments. The effect of two catechol-bearing TIQs, salsolinol (SAL) and tetrahydropapaveroline (THP), on the viability of melanotic or amelanotic melanoma cell lines was investigated. Both SAL and THP were well tolerated up to roughly 30 microM and became overtly toxic at higher concentrations, with SAL being better tolerated than THP. Intracellular activity of some antioxidant enzymes, tyrosinase and alpha-ketoglutarate dehydrogenase was also evaluated to assess the cell response to oxidative and metabolic challenge of TIQs treatment. Catalase and superoxide dismutase pre-treatment only partially prevented TIQs toxicity while a complete protection was obtained with N-acetylcysteine and GSH. TIQs were able to provoke upregulation of the scavenging enzymes catalase and DT-diaphorase and to determine a decrease of the alpha-ketoglutarate dehydrogenase activity. SAL and THP enhanced tyrosinase activity and melanin production, suggesting that they were indeed tyrosinase substrates leading to melanin formation. The results support the evidence that TIQs were toxic toward melanoma cells, leading to their death by necrosis. TIQs toxicity was likely due to increased oxidative stress by generation of reactive oxygen species and oxidative metabolites. Our study represents an intent to furnish an additional contribution for the comprehension of catechol cytotoxicity.
四氢异喹啉（TIQs）是在哺乳动物的尿液、中枢神经系统和一些外周组织中检测到的内源性生物碱化合物。目前尚无关于皮肤中TIQ水平的数据，尽管体外生化证据表明它们可能会发生自动氧化并产生活性氧，或者可能被酶转化为黑色素。研究了两种含儿茶酚的TIQs，即去甲猪毛菜碱（SAL）和四氢罂粟碱（THP）对黑色素瘤或无黑色素黑色素瘤细胞系活力的影响。SAL和THP在高达约30微摩尔的浓度下耐受性良好，在更高浓度下会明显产生毒性，SAL的耐受性比THP更好。还评估了一些抗氧化酶、酪氨酸酶和α-酮戊二酸脱氢酶的细胞内活性，以评估细胞对TIQs处理的氧化和代谢挑战的反应。过氧化氢酶和超氧化物歧化酶预处理只能部分预防TIQs的毒性，而N-乙酰半胱氨酸和谷胱甘肽能提供完全保护。TIQs能够引起清除酶过氧化氢酶和DT-黄递酶的上调，并导致α-酮戊二酸脱氢酶活性降低。SAL和THP增强了酪氨酸酶活性和黑色素生成，表明它们确实是导致黑色素形成的酪氨酸酶底物。结果支持了TIQs对黑色素瘤细胞有毒性，导致其坏死死亡的证据。TIQs的毒性可能是由于活性氧和氧化代谢产物的产生导致氧化应激增加。我们的研究旨在为理解儿茶酚细胞毒性提供更多贡献。
