Publication: Ultrastructural changes in rat livers perfused in vitro and in vivo with a high dose of methotrexate
Authors
Al-Ali, Saad Y. ; Hassan, Ibrahim M. ; Sadek, S.
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Publisher
Murcia : F. Hernández
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DOI
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info:eu-repo/semantics/article
Description
Abstract
Methotrexate is an antifolate that is widely
used in the treatment of malignant tumours and other
diseases. The present study was undertaken to examine
the short-term effects of high doses of methotrexate
(HD-MTX) on the ultrastructure and metabolic activity
of isolated rat livers. The authenticity of the druginduced
changes was substantiated by the concomitant
use of in vivo experiments.
Isolated rat livers were infused with HD-MTX via
the portal vein for 3 hours (total dose for each liver 2000
mg). For in vivo experiments, each rat received a single
intravenous injection of a maximum tolerated dose of
MTX (100 mg/kg body weight) that allowed the animals
to survive for 3 days. At the end of each experimental
period, MTX-treated and control livers were processed
for light microscopy (LM), scanning (SEM) and
transmission electron (TEM) microscopy. Oxygen
consumption and thyroxine metabolism were measured
in treated and control isolated livers.
With the exception of a few minor differences, the
structural changes in the hepatocytes after MTX
treatment in vitro and vivo were similar. There were
focal changes consisting of disruption of normal hepatic
plates and swelling and vacuolation of the hepatocytes,
with no clear evidence of restriction to a specific hepatic
zone. SEM revealed striking changes in the plasma
membrane, the microvillar system, intercellular
junctions and the sinusoidal endothelium. TEM revealed
disorganized endoplasmic reticulum, dispersion of the
polyribosomes, a variety of mitochondrial changes, and
glycogen redistribution. In MTX-treated isolated rat
livers, the uptake of tetraiodothyronine (T4) was not
affected, but triiodothyronine (T3) release was impaired. Oxygen consumption was increased in livers treated
with MTX.
Employing an organotypic liver perfusion model in
conjunction with the in vivo experiment and the use of SEM, TEM and hepatic thyroxine measurements, this
investigation revealed that infusion of HD-MTX induced
early ultrastructual changes in cell membrane,
intercellular junctions and cell organelles and
disturbance in the functional integrity of the hepatocytes
in isolated rat liver.
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