Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.37 (DNA methyltransferase)
 4,983 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hydrazine sulfate is a genotoxic hepatocarcinogen for the hamster. A study was conducted to follow changes in DNA maintenance methylation in selected genes in liver DNA during the 21-month induction of liver adenomas and hepatocellular carcinomas by demonstrating changes in restriction fragment length polymorphism. Male Syrian golden hamsters were exposed to hydrazine sulfate in the drinking water at three concentrations (170, 340 and 510 mg/l) shown previously to result in a dose-dependent induction of liver tumors. Liver DNA from animals exposed to the high concentration for 6, 12, 16, 20 and 21 months and animals exposed to the low or mid concentration for 21 months was digested with EcoRI, MspI, HindIII or BamHI, or a combination of one of these endonucleases and a methyl-sensitive restriction enzyme, HpaII or HhaI. The DNA digests were subjected to Southern analysis using a c-DNA probe for one of the following genes: DNA methyltransferase (DMT), c-Ha-ras, c-jun, c-fos, and c-myc proto-oncogenes, p53 tumor suppressor gene or gamma-glutamyltranspeptidase. Alteration in DNA restriction by methyl-sensitive endonucleases was detected in four (DMT, c-Ha-ras, p53 and c-jun) of the seven genes examined and as early as 6 months in animals exposed to the highest concentration of hydrazine sulfate; alteration of recognition sites in c-Ha-ras was also detected in DNA from animals exposed for 21 months to the intermediate concentration of hydrazine sulfate. Early changes in recognition sites, presumed to indicate altered methylation status of DNA cytosine and/or guanine mutations, were seen using c-DNA probes for DMT, c-Ha-ras and c-jun; in the p53 tumor suppressor gene alteration of such sites was a late event relevant to appearance of liver adenomas and hepatocellular carcinomas. Evidence for hypomethylation in the p53 and c-jun genes and hypermethylation of the c-Ha-ras and DMT genes is provided. This study supports the induction of site-specific hypomethylation and hypermethylation during the course of hydrazine carcinogenesis.
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PMID:Changes in methyl-sensitive restriction sites of liver DNA from hamsters chronically exposed to hydrazine sulfate. 900 10

DRH strain rats were established by inbreeding a closed colony of Donryu rats continuously fed the chemical hepatocarcinogen 3'-methyl-4-dimethylaminoazobenzene for over 10 years. They are highly resistant to chemical induction of liver cancer and preneoplastic lesions. We studied the genetic basis of DRH resistance to preneoplastic lesions by analyzing 108 (F344 x DRH)F2 male rats fed 3'-methyl-4-dimethylaminoazobenzene for 7 weeks. Five parameters of preneoplastic liver lesions were selected for quantitative analysis: (a) number of glutathione S-transferase placental form-positive foci per unit area of liver section; (b) percentage area occupied by the foci; (c) average size of foci; (d) glutathione S-transferase placental form mRNA level; and (e) gamma-glutamyltranspeptidase mRNA level. Furthermore, O6-methylguanine DNA methyltransferase and mannose 6-phosphatase/insulin-like growth factor 2 receptor mRNA levels were quantified. Composite interval mapping analysis showed that there were two remarkably significant clusters of quantitative trait loci affecting preneoplastic liver lesions on chromosomes 1 and 4. These clusters were designated collectively as Drh1 and Drh2, respectively. The functions of the recessive DRH allele of Drh1 and the semidominant DRH allele of Drh2 were to suppress the phenotypes of precancerous lesions. Each cluster showed two to three subpeaks in linkage likelihood plots, suggesting the presence of several closely linked quantitative trait loci affecting preneoplastic lesions. Possible candidate genes at each locus will be discussed. Expression of O6-methylguanine DNA methyltransferase and mannose 6-phosphatase/insulin-like growth factor 2 receptor did not affect DRH resistance to hepatocarcinogenesis, although they were polymorphic between DRH and F344 rats.
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PMID:Genetic resistance to chemical carcinogen-induced preneoplastic hepatic lesions in DRH strain rats. 1085 Apr 31