The pattern of methylated purines formed in DNA of intact and regenerating liver of rats treated with the carcinogen dimethylnitrosamine

Persistence of O 6-Ethylguanine in Rat-Brain DNA: Correlation with Nervous System-Specific Carcinogenesis by Ethylnitrosourea

“…Both in vivo and in vitro, the elimination of ethylated bases appears to be slower than that of their methylated homologues (38,39,4). For example, values of 13 hr (21) and 24 hr (22) have been published for the half-life of 06-methylguanine in adult liver DNA, whereas the corresponding value for 06-EtG in the present study approximated to 30 hr.…”

“…According to the present study, the stability of 06-EtG in vitro is, however, exceptionally high. In general, faster rates have been reported for the elimination of alkylated bases from DNA in vivo than during in vitro incubation (41,21,22,40). Both in vivo and in vitro, the elimination of ethylated bases appears to be slower than that of their methylated homologues (38,39,4).…”

“…Whereas the elimination rates from brain and liver DNA are similar for N7-ethylguanine (N7-EtG) and N3-ethyladenine (N3-EtA), respectively, brain DNA is characterized by a strongly reduced elimination rate for 06-ethylguanine (06-EtG). Alkylation of DNA guanine in the 06-position has recently received much attention as a highly mutagenic and potentially oncogenic lesion (17)(18)(19)(20)(21)(22)(23) DNA, RNA, and protein were isolated from the pooled tissue samples by a modified Kirby method (7). Samples of DNA (5-100 mg) were hydrolyzed in 0.1 N HCl (2 mg of DNA per ml) at 370 for 20 hr (18), neutralized, and concentrated to a volume of 5-10 ml.…”

Nitrosamines and Pesticides: A Special Report on the Occurrence of Nitrosamines as Terminal Residues Resulting From Agricultural Use of Certain Pesticides

“…However, it has been demonstrated (Lijinsky etal., 1968) that diazomethane itself is not an intermediate in the methylation of guanine by NDMPL in DNA or RNA in rat livers, The reactions with proteins in vitro by 14C-NDMA (Magee and Hultin, 1962) include methylation at the 1 and 3-positions of histidine, Some 14C-NDMk activity was also detected in the 3-carbon atom of serine, indicating that the carbon atoms from NDMA had entered the C1 metabolic pool. The main alkylation reaction of nucleic acids is at the N-7 position of guanine in RNA and DNA (Magee and Farber, 1962), although several other reactions have been noted including the methylation at the 1-and 3-position of adenine, the 1-position of cytosine, and the 0-6-position of guanine (Lawley et al,, 1968, Craddock, 1973, The alkylations of proteins and nucleic acids account for only a small percentage of the alkyl groups of NDMA, However, the latter reaction is widely believed to be the critical event in the carcinogenicity of nitrosanines, The correlation of carcinogenicity and the predominant methy)ation, N-7 of guanine, is not considered to be adequate and the arguments have been reviewed by Magee etal, (1975) and by Lijinsky (1976), It is now postulated that the alkylation at other sites, like the 0-6 position of guanine in nucleic acids, may be even more critical events (Loveless, 1969), In studying NDMA methylase activity and its inhibitors, Friedman et a.l. (1976) concluded that nitrosarcosin and nitrosodiethylamine suppressed the enzyme activity in rat liver, They also concluded that DNA alkylation by NDMA in lung and kidney may be mediated by different pathways than is RNA or protein alkylation in the liver, Unauthenticated Download Date | 6/20/19 3:00 AM Singer (1975) has reviewed the methylation of ribose as well as the esterification of internucleotide phosphodiesters.…”

Induction of tumours in intact and partially hepatectomized rats with ethyl methanesulphonate

“…It appears likely that 06-alkylguanine rather than 7-alkylguanine is relevant in carcinogenesis (Loveless, 1969). DMN and NMU give rise to both these methylated bases, whereas no 06-methylguanine was detectable in rat liver after treatment with MMS (Craddock, 1973b). A small amount was measured after treatment of DNA with MMS in vitro (Lawley and Shah, 1972), and in mice treated with MMS in vivo (Frei and Lawley, 1976 proportion of the products of reaction with nucleic acids (Shooter et al, 1974;Lawley, Orr and Jarman, 1975;Singer and Fraenkel-Conrat, 1975;Sun and Singer, 1975).…”