Inhibition
of 2-nitropropane-induced cellular proliferation, DNA synthesis
and histopathological changes by melatonin
Gamal H. El-Sokkary
Department of Zoology, Faculty of Science, Assiut University,
Assiut, 71516, Egypt.
Key
words:
2-Nitropropane;melatonin;cell proliferation;DNA synthesis;
histopathological changes;necrosis and degeneration
Submitted:
June 1, 2002
Accepted: June 14, 2002
ABSTRACT
OBJECTIVES:
2-Nitropropane (2-NP) is mutagenic in a number of short-term
mutagenicity assays in vitro and in vivo, and is a potent
hepatocarcinogen in rats. Many studies have determined that
differences in the metabolism and disposition of the chemicals
that produce mutagenicity were not responsible for their observed
carcinogenic differences, but that carcinogenicity correlated
with the ability of the respective isomer to induce cell proliferation
in the target organ.
METHODS:
Three groups of male rats (control, 2-NP-treated [4 mmol/kg]
and 2-NP + melatonin [10 mg/kg]) were used in the current
study. Cell proliferation was quantitated by incorporation
of 3H-thymidine, detected by autoradiography, into newly synthesized
DNA. Histopatholgical study was carried out to investigate
the morphological changes.
RESULTS:
Twenty four hours after 2-NP administration, there was an
increase in the labelling index (LI) and grain count per labelled
nucleus (GC/N) in the hepatocytes of 2-NP-injected rats versus
those of control animals. The increase was 69.5% in LI and
29.4% in GC/N. Melatonin treatment, 30 minutes preceding 2-NP,
reduced the increase in LI (44.4%) and GC/N (20.7%) when compared
with 2-NP-treated rats. Histopathology revealed multiple focal
areas of necrosis in the liver following 2-NP injection. In
the lung, there was a mucinous degeneration of the bronchial
epithelium. Melatonin treatment restored the histopathological
changes in both the liver and lung and they are more or less
normal.
CONCLOSION:
Overall, these results seem to indicate that the stimulatory
effect of 2-NP on the cellular proliferation and the rate
of DNA synthesis in the liver may be one of mechanisms by
which the carcinogen induces its carcinogenic action. Also,
melatonin treatment strongly protects the studied organs against
the toxic effect of 2-NP.
ABBERVIATIONS:
·OH
(hydroxyl radical)
LOO· (peroxyl radical)
O2·– (superoxide anion)
NO (nitric oxide)
ONOO– (peroxynitrite anion)
Introduction
2-Nitropropane (2-NP) has been widely used in printing inks,
adhesives, rocket propellants, paint and varnish removers, as
a gasoline additive, and in the manufacture of nitrocellulose
and chlorinated rubber [1]. They also reported that occupational
exposure to 2-NP occurs principally in industrial construction,
highway maintenance, ship building, furniture manufacture, and
plastic production. The principal target organ of 2-NP toxicity
is the liver. Following i.p. injection, 2-NP and its carbon-containing
metabolites are concentrated initially in fat and subsequently
in bone marrow, adrenal glands and other internal organs [2,3].
It is thought that generation of reactive oxygen species via
the metabolism of 2-NP-nitronate to acetone and nitrite plays
an important role for the carcinogenic effect [4].
It was hypothesized that the high rate of DNA synthesis might
be related to the high incidence of tumors in liver, lung and
other organs induced by exposure to carcinogens [5,6]. However,
there is no evidence that the DNA synthesis rate is directly
related to carcinogenesis. It was suggested that the cell cycle-dependent
variation in susceptibility to hepatocarcinogenesis might be
due to the efficient removal of potentially carcinogenic lesions
from DNA. Additionally, it was reported that the activity of
O6-methylguanine methyltransferase, which can repair alkylated
bases in DNA, might be increased in the early S phase but be
rapidly exhausted [7]. An increase in cell proliferation was
observed following exposure to 2-NP [8,9]. These results indicate
that cell proliferation may be requisite for expression of chemical-induced
mutagenicity in vivo and thereby accommodate expression of carcinogenicity.
The main secretory product of the pineal gland, melatonin, has
been shown to function as a free radical scavenger and antioxidant
[10,11]. It is also an inhibitor of the cell cycle, thereby
increasing the number of MCF-7 cells in G1 and reducing the
percentage of cells in S phase two-fold [12]. El-Sokkary [13]
reported that melatonin has an anticancer function in the mammary
glands and liver when it was injected after the chemical carcinogen
9,10- dimethyl-1,2-benzanthracene (DMBA) at different periods.
In addition, melatonin exerted an inhibitory effect on the rate
of DNA synthesis and the rate of proliferative activity as well
as it prolonged the cell cycle duration after DMBA administration.
The current study was designed to investigate the efficacy of
melatonin as an antioxidant and anticancer in reducing the cellular
proliferation and histopathological changes induced by 2-NP
in rats. Also to demonstrate a mechanism likely to mediate the
prevention of cellular degeneration by melatonin.
...
...
|
