Potential utility of xenobiotic mitogens in the context of liver regeneration in the elderly and living-related transplantation

COLUMBANO, AMEDEO;Simbula M;PIBIRI, MONICA;PERRA, ANDREA;PISANU, ADOLFO;Uccheddu A;LEDDA, GIOVANNA MARIA

2008-01-01

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Abstract

Although liver regeneration occurring after partial hepatectomy (PH) is greatly reduced in aged mice, liver hyperplasia induced by xenobiotic mitogens was found to be age independent. Here, we investigated the potential utility of mitogens in stimulating liver regeneration in old mice subjected to two-third PH. Although virtually no hepatocytes entered S phase 48 h after PH, pretreatment (2 h prior to surgery) with 1,4-bis(2-(3,5-dichloropyridyloxy)benzene (TCPOBOP), a ligand of constitutive androstane receptor, induced an increase of bromodeoxyuridine incorporation and enhanced the expression of cyclin D1, cyclin A and proliferating cell nuclear antigen . Next, we investigated the potential utility of mitogens in the context of donor conditioning prior to living-related transplantation. Three days after TCPOBOP administration to intact young mice, an almost doubling of the liver mass and DNA content occurred; the regenerative response to two-third resection of the TCPOBOP-induced hyperplastic liver was similar to that of mice subjected to PH alone, suggesting that an increased liver mass at the time of surgery does not inhibit the regenerative capacity. The present results suggest that mitogen-induced hyperplasia is a promising tool in conditions characterized by reduced regenerative capacity, such as in the elderly, or when a rapid increase of liver mass is required, such as in living-related transplantation.