The effects of three of the most widely used
histamine H2-receptor antagonists,
cimetidine,
ranitidine and
famotidine, on liver cell growth were studied in vitro using adult rat hepatocytes in primary culture, because these antagonists are commonly given to patients with
hepatic cirrhosis or
fulminant hepatic failure for protection against
peptic ulcers and
gastrointestinal hemorrhage. At their clinically effective concentrations in the blood (0.5-5 micrograms/ml
cimetidine, 0.25-2.5 micrograms/ml
ranitidine and 0.05-0.5 microgram/ml
famotidine), these three antagonists did not have any effect on replicative
DNA synthesis either in the presence or absence of
insulin plus
epidermal growth factor (
EGF). However, unexpectedly
DNA synthesis stimulated by
insulin and
EGF was found to be enhanced by 0.05-0.5 mg/ml
cimetidine, although it was unaffected or inhibited by
ranitidine and
famotidine at the concentrations tested.
Cimetidine caused maximal enhancement of 1.5-2 times the control level of
DNA synthesis at a concentration of 0.25 mg/ml.
Cimetidine also had an enhancing effect at submaximal concentrations of
insulin and
EGF, but neither
cimetidine nor the other antagonists had any stimulatory effect on
DNA synthesis in the absence of
insulin plus
EGF. This enhancement of
DNA synthesis by
cimetidine resulted in significant increase in the total
DNA content of the hepatocytes in culture. Under the conditions used,
cimetidine had the lowest toxicity of these three antagonists and
ranitidine the highest, as judged from data on
DNA synthesis and the total
protein content of cultured hepatocytes, leakage of
aminotransferases from the cells and morphological observations.