Carcinogenesis, Vol 19, 1521-1527, Copyright © 1998 by Oxford University Press
NJ Plant, NJ Horley, M Dickins, S Hasmall, CR Elcombe and DR Bell
The coordinate regulation of DNA synthesis and suppression of apoptosis was
investigated in a rat hepatocyte cell culture system which supports high
level induction of DNA synthesis by the peroxisome proliferator,
methylclofenapate (MCP) (Plant, N.J. et al., 1998, Carcinogenesis, 19,
925-931). The peroxisome proliferators are hepatocyte mitogens in
chemically defined media: glucocorticoid-induced PPARalpha is linked to
peroxisome proliferator mitogenesis (Plant, N.J. et al., 1998,
Carcinogenesis, 19, 925-932). Phenobarbital (PB) induced moderate induction
of DNA synthesis (200-300% of control), but the peak of induction was 40 h
after treatment. In hepatocytes that had undergone DNA synthesis, PB
increased the proportion of binucleates by 200-300%. Both PB and MCP were
able to suppress apoptosis in a dose-dependent manner, while the endogenous
mitogen epidermal growth factor failed to suppress apoptosis. The
suppression of apoptosis by MCP was reversible; withdrawal of MCP led to
rapid induction of apoptosis. The presence of hydrocortisone is required
for suppression of apoptosis by peroxisome proliferators, but not for PB.
MCP failed to suppress apoptosis in primary cultures of guinea-pig
hepatocytes. Comparison of the stability of hepatocytes labelled with
bromodeoxyuridine (BrdUrd) and [3H]thymidine revealed that approximately
40% of cells labelled with BrdUrd were lost over a period of 14 days,
whereas cells labelled with thymidine remained stable over this period.
Hepatocytes were therefore treated with MCP, labelled with [3H]thymidine,
maintained for 14 days, and peroxisome proliferator withdrawn. While the
apoptotic index in unlabelled cells was 1.7%, no apoptosis was detected in
labelled cells. In order to compare the mechanism of suppression of
apoptosis, hepatocytes were cultured in the presence of either PB or MCP
for 14 days. When MCP was substituted for PB in cells cultured in the
presence of PB, the monolayer was maintained, but when PB was used to
replace MCP in cells cultured in the presence of MCP, the monolayer of
hepatocytes degenerated rapidly. The results demonstrate mechanistic
differences in the coordinate regulation of cell growth and apoptosis in
hepatocytes by PB and MCP.
ARTICLES
The coordinate regulation of DNA synthesis and suppression of apoptosis is differentially regulated by the liver growth agents, phenobarbital and methylclofenapate
School of Biological Sciences, Molecular Toxicology Division, University of Nottingham, University Park, UK.
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