Arsenite induced oxidative damage in mouse liver is associated with increased cytokeratin 18 expression.
Cytokeratins (CK) constitute a family of cytoskeletal intermediate filament proteins that are typically expressed in epithelial cells. An abnormal structure and function are effects that are clearly related to liver diseases as non-alcoholic steatohepatitis, cirrhosis and hepatocellular carcinoma. We have previously observed that sodium arsenite (SA) induced the synthesis of CK18 protein and promotes a dose-related disruption of cytoplasmic CK18 filaments in a human hepatic cell line. Both abnormal gene expression and disturbance of structural organization are toxic effects that are likely to cause liver disease by interfering with normal hepatocyte function. To investigate if a disruption in the CK18 expression pattern is associated with arsenite liver damage, we investigated CK18 mRNA and protein levels in liver slices treated with low levels of SA. Organotypic cultures were incubated with 0.01, 1 and 10 microM of SA in the absence and presence of N-acetyl cysteine (NAC). Cell viability and inorganic arsenic metabolism were determined. Increased expression of CK18 was observed after exposure to SA. The addition of NAC impeded the oxidative effects of SA exposure, decreasing the production of thiobarbituric acid-reactive substances and significantly diminishing the up regulation of CK18 mRNA and protein. Liver arsenic levels correlated with increased levels of mRNA. Mice treated with intragastric single doses of 2.5 and 5 mg/kg of SA showed an increased expression of CK18. Results suggest that CK18 expression may be a sensible early biomarker of oxidative stress and damage induced by arsenite in vitro and in vivo. Then, during SA exposure, altered CK expression may compromise liver function.
Gonsebatt
M E
ME
Dep. Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, UNAM, AP 70-228, Ciudad Universitaria, México DF, 04510, México.
Del Razo
L M
LM
Cerbon
M A
MA
Zúñiga
O
O
Sanchez-Peña
L C
LC
Ramírez
P
P
D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D053538:Keratin-18 / Q000096:biosynthesis* / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D018053:Arsenites; D053538:Keratin-18; D012333:RNA, Messenger; D017392:Thiobarbituric Acid Reactive Substances; C015001:arsenite