ABSTRACT
The methylation by DMPT and MNU of DNA from rat liver and brain was investigated at various developmental stages. Following a single sc injection of [14C]DMPT (100 mg/kg body wt, 15 hr survival time) in pregnant rats (21st day of gestation), the extent of methylation of purine bases was similar in fetal liver and brain. During postnatal growth, this treatment resulted in an increasingly preferential methylation of liver DNA. In 30-day-old BD-IX rats, the concentration of 7-methylguanine in liver was approximately eight times higher than in brain DNA. This suggested that during prenatal development, both liver and brain DNA are transplacentally methylated by a proximate carcinogen produced by maternal organs. After a single ip injection of [3H]MNU (10 mg/kg body wt) to 10-day-old rats, O6-methylguanine was more rapidly removed from hepatic than from cerebral DNA. Within 1 week after the injection, the brain-to-liver ratio for 06-methylguanine increased from 1.4 to 98. These results are compatible with the hypothesis that the deficiency of various organs for repair excision of O6-alkylguanine from DNA correlates with their susceptibility to malignant transformation by monofunctional alkylating carcinogens.
Subject(s)
Maternal-Fetal Exchange , Methylnitrosourea/toxicity , Neoplasms, Experimental/chemically induced , Nervous System Diseases/chemically induced , Nitrosourea Compounds/toxicity , Triazenes/toxicity , Animals , Brain/metabolism , DNA/metabolism , DNA Repair/drug effects , Female , Fetus/metabolism , Guanine/analogs & derivatives , Guanine/metabolism , Liver/metabolism , Methylation , Methylnitrosourea/metabolism , Pregnancy , Rats , Triazenes/metabolismABSTRACT
The formation and persistence of methylated purines was determined in mice that received a single s.c. injection of 1,2-[14C]dimethylhydrazine (15 mg/kg) and were allowed to survive for 12 or 60 hr. In mice with a low susceptibility to dimethylhydrazine-induced colon carcinogenesis (C57BL/Ha), concentrations of 7-methylguanine and O6-methylguanine in DNA of colon, ileum, and kidney were 40 to 60% less than in mice with a high incidence of colonic tumors (ICR/Ha). In hepatic DNA the extent of methylation was higher in C57BL/Ha than in ICR/Ha mice. The rate of loss of methylated purines from colon DNA was similar in both strains. In all organs investigated the metabolic incorporation of 14C into normal DNA bases was lower in C57BL/Ha than in ICR/Ha mice. It is concluded that the low carcinogenic response of C57BL/Ha mice is due to the smaller extent of initial alkylation of colon DNA, which probably reflects differences in the enzymic metabolism of the parent carcinogen.
Subject(s)
Colonic Neoplasms/etiology , DNA/metabolism , Dimethylhydrazines/toxicity , Methylhydrazines/toxicity , Animals , Biotransformation , Colon/metabolism , Dimethylhydrazines/metabolism , Ileum/metabolism , Kidney/metabolism , Liver/metabolism , Male , Methylation , Mice , Mice, Inbred C57BL , Mice, Inbred ICR , Neoplasms, Experimental/etiology , Purines/metabolism , Species SpecificityABSTRACT
The persistence of O6-methylguanine produced by a single dose of N-methyl-N-nitrosourea (MNU) was determined in DNA of various murine tissues and compared with the location of tumours induced by MNU and related alkylating carcinogens in this species. A/J and C3HeB/FeJ mice received a single intravenous injection of MNU (10 mg/kg) and were killed at different time intervals ranging from 4 h to 7 days. The rate rate of loss of O6-methylguanine from brain DNA was considerably slower than from liver DNA; tumours have been found in both organs after administration of MNU and other alkylnitrosoureas. There was no difference in the rate of excision from cerebral DNA of A/J and C3HeB/FeJ mice, although these strains differ significantly in their susceptibility to the neurooncogenic effect of MNU and related carcinogens. Excision of O6-methylguanine from hepatic DNA was significantly slower in A/J than in C3HeB/FeJ mice; both strains habe been found to develop hepatic carcinomas following MNU administration. Seven days after the injection of 3H-MNU, O6-methylguanine concentrations were highest in brain and lung DNA, lowest in the liver, and intermediate in kidney, spleen, small intestine and stomach. The lung is a principal target organ for tumour induction by MNU and other carcinogens in mice; however, neural tumours are usually induced at a low incidence. The results obtained do not contradict the hypothesis that O6-alkylation of guanine in DNA is a critical event in the initiation of tumour induction by alkylating agents. However, the location of tumours produced in mice does not seem to depend solely on the formation and persistence of O6-alkylguanine in DNA.