title: Oxidative DNA damage and glioma cell death induced by tetrahydropapaveroline.
abstract: A series of naturally occurring isoquinoline alkaloids, besides their distribution in the environment and presence in certain food stuffs, have been detected in human tissues including particular regions of brain. An example is salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline) that not only induces neuronal cell death, but also causes DNA damage and genotoxicity. Tetrahydropapaveroline [THP; 6,7-dihydroxy-1-(3',4'-dihydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline], a dopamine-derived tetrahydroisoquinoline alkaloid, has been reported to inhibit mitochondrial respiration and is considered to contribute to neurodegeneration implicated in Parkinson's disease. Since THP bears two catechol moieties, the compound may readily undergo redox cycling to produce reactive oxygen species (ROS) as well as toxic quinoids. In the present study, we have examined the capability of THP to cause oxidative DNA damage and cell death. Incubation of THP with phiX174 supercoiled DNA or calf thymus DNA in the presence of cupric ion caused substantial DNA damage as determined by strand scission or formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo), respectively. THP plus copper-induced DNA damage was ameliorated by some ROS scavengers/antioxidants and catalase. Treatment of C6 glioma cells with THP led to a concentration-dependent reduction in cell viability, which was prevented by the antioxidant N-acetyl-L-cysteine. When these cells were treated with 10microM THP, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) were rapidly activated via phosphorylation, whereas activation of extracellular signal-regulated protein kinase (ERK) was inhibited. Furthermore, pretreatment with inhibitors of JNK and p38 MAPK rescued the glioma cells from THP-induced cytotoxicity, suggestive of the involvement of these kinases in THP-induced C6 glioma cell damage.
authors.affiliation: Department of Neuroscience, Graduate School of East-West Medical Science, Kyung Hee University, Yongin-si, Kyungki-do, South Korea.
authors.forename: Yunjo
authors.initials: Y
authors.lastname: Soh
authors.forename: Mi-Hyun
authors.initials: MH
authors.lastname: Shin
authors.forename: Jeong-Sang
authors.initials: JS
authors.lastname: Lee
authors.forename: Jung-Hee
authors.initials: JH
authors.lastname: Jang
authors.forename: Ok Hee
authors.initials: OH
authors.lastname: Kim
authors.forename: Hoil
authors.initials: H
authors.lastname: Kang
authors.forename: Young-Joon
authors.initials: YJ
authors.lastname: Surh
mesh_terms: D000818:Animals; D010584:Bacteriophage phi X 174 / Q000235:genetics*; D002417:Cattle; D016923:Cell Death / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003300:Copper / Q000494:pharmacology; D004247:DNA / Q000187:drug effects / Q000235:genetics; D004249:DNA Damage / Q000187:drug effects; D004279:DNA, Viral / Q000235:genetics*; D005910:Glioma / Q000473:pathology*; D005978:Glutathione / Q000378:metabolism; D006147:Guanine / Q000031:analogs & derivatives* / Q000032:analysis; D006801:Humans; D013765:Tetrahydropapaveroline / Q000633:toxicity*; D014407:Tumor Cells, Cultured
chemical_list: D004279:DNA, Viral; D013765:Tetrahydropapaveroline; C024829:8-hydroxyguanine; D006147:Guanine; D003300:Copper; D004247:DNA; D005978:Glutathione