The effect of serum from liver cancer patients on the growth and function of primary and immortalised hepatocytes.
A limiting factor in the efficacy of bioartificial liver (BAL) for the treatment of liver failure is the toxicity of the patients' serum to the hepatocytes in the device. This study investigates the interaction of liver cancer patient serum with primary and immortalised rat hepatocytes. Liver cancer serum increased the growth rate of immortalised hepatocytes, without affecting reduced glutathione levels. The activities of DT-diaphorase and pi glutathione-S-transferase (GST), enzymes associated with de-differentiation, were also increased. Exposure of primary hepatocytes to liver cancer serum resulted in a decrease in cytochrome P450 (CYP) content, and in P450 dependent metabolism of testosterone. Formation of 2-alpha- and 6-beta- hydroxy testosterone was decreased. These reactions are predominantly associated with CYP 2C11 and 3A1 respectively in normal rat liver. The activity of total GST was also decreased, although that of the pi isoenzyme of GST was not affected. Our results suggest that exposure of hepatocytes in a bioreactor to liver cancer patient serum will result in overgrowth of cells, if proliferating cells are being used, and in de-differentiation. The serum may have to be pretreated with adsorbants to remove toxins prior to BAL treatment.
Grant
M H
MH
Bioengineering Unit, University of Strathclyde, Glasgow, Scotland. m.h.grant@strath.ac.uk
Rodgers
E H
EH
Anderson
K
K
Haydon
G H
GH
Hayes
P C
PC
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005978:Glutathione / Q000097:blood; D008113:Liver Neoplasms / Q000097:blood* / Q000201:enzymology*; D019164:Liver, Artificial / Q000592:standards*; D051381:Rats; D016896:Treatment Outcome
D003577:Cytochrome P-450 Enzyme System; D005978:Glutathione