Ja. Beamand et al., LACK OF EFFECT OF COUMARIN ON UNSCHEDULED DNA-SYNTHESIS IN PRECISION-CUT HUMAN LIVER SLICES, Food and chemical toxicology, 36(8), 1998, pp. 647-653
In this study the effect of coumarin on unscheduled DNA synthesis (UDS
) in precision-cut human liver slices has been examined. Liver slices
from tissue samples from four donors were cultured for 24 hr in medium
containing [H-3]thymidine and 0-5.0 mM coumarin using a dynamic organ
culture system and processed for autoradiographic evaluation of UDS.
As positive controls liver slices were also cultured with three known
genotoxic agents, namely 0.02 and 0.05 mM 2-acetylaminofluorene (2-AAF
), 0.002 and 0.02 mM aflatoxin B-1 (AFB(1)) and 0.005 and 0.05 mM 2-am
ino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). UDS was quantified
as the net grain count in centrilobular hepatocytes and as the percen
tage of centrilobular hepatocyte nuclei with more than five net grains
. Compared with control liver slice cultures, treatment with 0.05-5.0
mM coumarin had no effect on UDS. In contrast, treatment with 0.02 and
0.05 mM 2-AAF, 0.002 and 0.02 mM AFB(1) and 0.005 and 0.05 mM PhIP pr
oduced significant increases in the net grain counts of centrilobular
hepatocytes. The greatest induction of UDS was observed in liver slice
s treated with 0.05 mM PhIP. Treatment with 2-AAF, AFB(1) and PhIP als
o produced significant increases in the number of centrilobular hepato
cyte nuclei with more than five net grains. At the concentrations exam
ined neither coumarin, 2-AAF, AFB1 nor PhIP had any significant effect
on replicative DNA synthesis in 24 hr cultured human liver slices. Th
ese results demonstrate that coumarin does not induce UDS in cultured
human liver slices. However, all three positive control compounds prod
uced marked significant increases in UDS, thus confirming the function
al viability of the human liver slice preparations used in this study.
The results of this study suggest that coumarin is not a genotoxic ag
ent in human liver. (C) 1998 Elsevier Science Ltd. All rights reserved