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Genetic variation of GSTM1, GSTT1 and GSTP1 genes in a South Indian population.The glutathione S transferase (GST) family of enzymes play a vital role in the phase II biotransformation of environmental carcinogens, pollutants, drugs and other xenobiotics. GSTs are polymorphic and the polymorphisms in GST genes have been associated with cancer susceptibility and prognosis. Moreover, distinct ethnic differences have been observed in the type and frequency of GST gene polymorphisms. Hence, the present study was aimed to determine the frequencies of GSTM1, GSTT1 and GSTP1 polymorphisms in 255 healthy random volunteers from South India. The GSTM1 and GSTT1 genotypes were determined by PCR and GSTP1 by PCR-RFLP using peripheral blood DNA.The GSTM1 and GSTT1 null genotype frequencies were found to be 22.4% and 17.6% respectively. The GSTP1 allelic frequency was 0.78 for the Ile allele and 0.22 for the Val allele and the genotype frequency was 58.4% for Ile/Ile, 38.4% for Ile/Val, and 3.1% for Val/Val. Comparison of the frequencies of GST polymorphisms observed in the present study with other Indian and world populations revealed a distinctive nature of the South Indian population with respect to polymorphims at the GST gene loci. A better understanding of carcinogen metabolizing gene distribution should contribute to risk assessment of humans exposed to environmental carcinogens.
Lack of promoting effects of phenobarbital at low dose on diethylnitrosamine-induced hepatocarcinogenesis in TGF-alpha transgenic mice.Phenobarbital (PB), a rodent non-genotoxic carcinogen, showed hormesis, biphasic effects on rat liver carcinogenesis. To test the hypothesis that the hormesis earlier observed for PB induced hepatocarcinogenesis might also exist in the TGF-alpha transgenic mice model, one which is highly susceptible to carcinogenesis, the carcinogenic or promotion effects of a wide range of phenobarbital (PB) concentrations were investigated. Two weeks after a single i.p. dose of 5 mg /kg bw of diethylnitrosamine (DEN) to 15 day old mice, animals were treated with diet containing PB at doses of 0, 2, 15 or 500 ppm. The incidence and multiplicity of tumors, including hepatocellular adenomas and carcinomas, were significantly increased by the high dose of PB, but no significant difference among the groups receiving 2 and 15 ppm for liver tumors when compared to DEN alone group. The proliferating cell nuclear antigen indices for liver tumors and surrounding hepatocytes in high dose PB treated mice were significantly increased, but no change was noted at the lower doses. The total cytochrome P450 content in the liver was also elevated by 500 ppm of PB, while hepatic 8-OHdG levels demonstrated no significant change. In conclusion, PB at high dose enhances DEN-induced hepatocarcinogenesis in TGF-alpha transgenic mice, but low doses lack any significant effects. One possible mechanism of phenobarbital carcinogenicity might be influenced by cytochrome P450 system exhibiting a strong promoting activity for liver of mice.
Tea-induced apoptosis in human leukemia K562 cells as assessed by comet formation.Programmed cell death or apoptosis is a physiological process by which genetically damaged cells or undesired cells can be eliminated. Various morphological and molecular changes undergoing during the process of apoptosis are the formation of apoptotic blebs of the cell membrane, cell shrinkage, condensation of chromatin and the disruption of deoxyribonucleic acid (DNA) into typical fragments of multiples of 180 base pairs. These changes can be detected in a number of ways. DNA ladder formation, which is observed following gel electrophoresis technique although is widely accepted but does not reflect the DNA breakdown in individual cell and also may miss contributions from small sub-populations in a heterogeneous cell population. Alkaline comet assay as measured by single cell gel electrophoresis, on the other hand, accurately measures DNA fragmentation on a single cell level and allows analysis of subpopulation of cells. The assay was originally developed for measuring DNA damage of cells exposed to any genotoxic agent. However, the comet image generated by an apoptotic cell is different from that obtained with a cell treated for a short time with a genotoxic agent. Correlation of comet formation with various other established parameters of apoptosis is very important. The present study aims to correlate different features of apoptosis with the formation of comet tail in human leukemia K-562 cells using tea extracts. Apoptosis as measured by formation of apoptotic bodies, flow cytometric analysis, activation of caspase 3 and 8, and expressions of apoptosis related genes such as bcl-2 and bax showed high degree of correlation with comet tail moment. This indicates that comet assay can accurately reflect measure of DNA fragmentation and hence can be used to detect a cell undergoing apoptosis.