Induction of glutathione depletion, p53 protein accumulation and cellular transformation by tetrachlorohydroquinone, a toxic metabolite of pentachlorophenol.
Glutathione (GSH) conjugate formation with tetrachlorohydroquione (TCHQ) and the GSH content in vivo were measured by capillary zone electrophoresis. A more than 60% depletion of GSH content was found in liver tissue of mice treated with TCHQ. In addition, p53 protein accumulation and DNA fragmentation was induced by TCHQ. A two-stage model of chemical transformation of mouse embryonic fibroblasts was used to elucidate the transformation activity of TCHQ in vitro, and a 33% foci formation efficiency was found at the concentration of 5 microM. GSH depletion caused by TCHQ could abolish the protective ability of the cell against reactive oxygen species provided by GSH. When DNA was damaged, p53 protein accumulated in the nucleus and, in the case of severe damage, initiated apoptosis. TCHQ's ability to cause GSH depletion and DNA damage may play a role in the cytotoxic and genotoxic properties of its metabolic precursor, PCP.
Wang
Y J
YJ
Institute of Biochemistry, College of Medicine, National Taiwan University, Taipei, ROC.
Ho
Y S
YS
Chu
S W
SW
Lien
H J
HJ
Liu
T H
TH
Lin
J K
JK
D016475:3T3 Cells / Q000187:drug effects; D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002273:Carcinogens / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D002875:Chromosomes / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D019075:Electrophoresis, Capillary; D005978:Glutathione / Q000172:deficiency*; D006873:Hydroquinones / Q000633:toxicity*; D051379:Mice; D008809:Mice, Inbred C3H; D010416:Pentachlorophenol / Q000378:metabolism*; D010575:Pesticides / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D002273:Carcinogens; D006873:Hydroquinones; D010575:Pesticides; D016159:Tumor Suppressor Protein p53; C044578:2,3,5,6-tetrachlorohydroquinone; D010416:Pentachlorophenol; D005978:Glutathione; D000111:Acetylcysteine