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NEUROENDOCRINOLOGY LETTERS
including Psychoneuroimmunology, Neuro
psychopharmacology,
Reproductive Medicine, Chronobiology
and Human Ethology
ISSN 0172–780X

NEL Vol.23 No.4, August 2002

ORIGINAL ARTICLE
Inhibition of 2-nitropropane-induced cellular proliferation,
DNA synthesis and histopathological changes by melatonin

2002; 23:335340
pii: NEL230402A08
PMID: 12195237

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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.

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