Ethanol induces redox-sensitive cell-cycle inhibitors and inhibits liver regeneration after partial hepatectomy.
BACKGROUND
Doses of ethanol (EtOH) that are not overtly cytotoxic inhibit mitogen-induced hepatocyte proliferation and delay liver regeneration after 70% partial hepatectomy (PH). The mechanisms for this are poorly understood. This study evaluates the hypothesis that EtOH inhibits hepatocyte proliferation after PH by inducing redox-sensitive factors, such as p38 mitogen-activated protein kinase (MAPK) and p21 (WAF1/CIP1), that protect cells from oxidative stress but prevent cell-cycle progression by inhibiting cyclin D1.


METHODS
Mechanisms that regulate the transition from the prereplicative G1 phase of the cell cycle into S phase were compared in EtOH-fed mice and normal pair-fed mice after PH.


RESULTS
Prior EtOH exposure significantly increases p38 MAPK and p21 after PH. This is accompanied by reduced expression of cyclin D1 messenger RNA and protein, increases in other cell-cycle regulators (such as signal transducer and activator of transcription-3 and p27) that are normally inhibited by cyclin D1, and hepatocyte G1 arrest.


CONCLUSIONS
EtOH amplifies G1 checkpoint mechanisms that are induced by oxidative stress and promotes hepatic accumulation of factors, including p38 MAPK, p21, and signal transducer and activator of transcription-3, that enhance cellular survival after oxidant exposure. Therefore, cell-cycle inhibition may be an adaptive response that helps EtOH-exposed livers survive situations, such as PH, that acutely increase reactive oxygen species in hepatocytes.
Koteish
Ayman
A
Department of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
Yang
Shiqi
S
Lin
Huizhi
H
Huang
Jiawen
J
Diehl
Anna Mae
AM
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects* / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D000431:Ethanol / Q000494:pharmacology*; D006131:Growth Inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D006498:Hepatectomy / Q000379:methods; D008115:Liver Regeneration / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
D006131:Growth Inhibitors; D000431:Ethanol; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases