Inhibition of 2-nitropropane-induced cellular proliferation, DNA synthesis and histopathological changes by melatonin.
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.
CONCLUSION: 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....