Cytotoxic effect of 7alpha-hydroxy-4-cholesten-3-one on HepG2 cells: hypothetical role of acetaldehyde-modified delta4-3-ketosteroid-5beta-reductase (the 37-kd-liver protein) in the pathogenesis of alcoholic liver injury in the rat

Hepatology : Official Journal of the American Association for the Study of Liver Diseases
R C LinX Du

Abstract

We recently identified delta4-3-ketosteroid-5beta-reductase as the 37 kd liver protein which is highly susceptible to acetaldehyde modification in rats continuously fed alcohol. The 5beta-reductase is a key enzyme involved in bile acid synthesis. We report here that the ability to degrade 7alpha-hydroxy-4-cholesten-3-one (HCO) was lower in the liver cytosol of alcohol-fed rats than in control animals, suggesting an inhibition of the 5beta-reductase enzyme activity by acetaldehyde modification. We also showed that HCO exhibited a time- and concentration-dependent cytotoxicity to HepG2 cells. HCO cytotoxicity was noticeable at a concentration of 2.5 microg/mL. When 10 microg/mL of HCO was added to confluent cell monolayers, 57% and 37% of cells remained viable after 24 and 48 hours of treatment. The decrease in cell viability was accompanied by an increased lactic dehydrogenase activity in the culture medium. DNA extracted from HCO-treated cells showed no evidence of DNA fragmentation when analyzed by agarose gel electrophoresis. Staining with propidium iodide showed no nuclear condensation in cells. Thus, cell death by HCO treatment was caused by necrosis and not by apoptosis. Various agents, including, serum proteins, hormones,...Continue Reading

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Citations

Jan 9, 2001·Archives of Biochemistry and Biophysics·K S JeongB J Song
Feb 24, 2001·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·A MaranR T Turner
Dec 28, 2010·Chemico-biological Interactions·Rebekka MindnichTrevor M Penning
May 12, 2009·The Journal of Steroid Biochemistry and Molecular Biology·Orazia M GranataGiuseppe Carruba

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