Ethanol induces redox-sensitive cell-cycle inhibitors and inhibits liver regeneration after partial hepatectomy.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Koteish, A; Yang, S; Lin, H; Huang, J; Diehl, AM

Published Date

  • November 2002

Published In

Volume / Issue

  • 26 / 11

Start / End Page

  • 1710 - 1718

PubMed ID

  • 12436061

Pubmed Central ID

  • 12436061

International Standard Serial Number (ISSN)

  • 0145-6008

Digital Object Identifier (DOI)

  • 10.1097/01.ALC.0000036923.77613.59

Language

  • eng

Conference Location

  • England