Effect of partial hepatectomy on removal of <i>O</i>6-methylguanine from alkylated DNA by rat liver extracts

Pegg, Anthony E.; Perry, Wayne; Bennett, Richard A. O.

doi:10.1042/bj1970195

Cited by 71 publications

(19 citation statements)

References 32 publications

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“…3H-labeled methylated DNA was prepared by the reaction of calf thymus DNA (Sigma Chemical Co., St. Louis, Mo.) with N-[3H]methyl-Nnitrosourea (1.0 Ci/mmol; Amersham, Buckinghamshire, United Kingdom) (37). The extracts were assayed by incubation at 37°C for 15 min of a reaction mixture containing 35 mM N-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES)-KOH buffer (pH 7.8), 10 mM dithiothreitol, 500 ,uM spermidine hydrochloride, 20 ,ug of bovine serum albumin, 50 ,ug of 3H-labeled methylated DNA containing 2.27 pmol of 06-MeG adduct, and the crude extracts in a total volume of 0.4 ml (25).…”

Section: Methodsmentioning

confidence: 99%

Cloning and characterization of the Salmonella typhimurium ada gene, which encodes O6-methylguanine-DNA methyltransferase

et al. 1991

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The ada gene of Escherichia coli encodes O6-methylguanine-DNA methyltransferase, which serves as a positive regulator of the adaptive response to alkylating agents and as a DNA repair enzyme. The gene which can make an ada-deficient strain of E. coli resistant to the cell-killing and mutagenic effects of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) has been cloned from Salmonella typhimurium TA1538. DNA sequence analysis indicated that the gene potentially encoded a protein with a calculated molecular weight of 39,217. Since the nucleotide sequence of the cloned gene shows 70% similarity to the ada gene of E. coli and there is an ada box-like sequence (5'-GAATTAAAACGCA-3') in the promoter region, we tentatively refer to this cloned DNA as the adaST gene. The gene encodes Cys-68 and Cys-320, which are potential acceptor sites for the methyl group from the damaged DNA. The multicopy plasmid carrying the adaST gene significantly reduced the frequency of mutation induced by MNNG both in E. coli and in S. typhimurium. The AdaST protein encoded by the plasmid increased expression of the ada'-lacZ chromosome fusion about 5-fold when an E. coli strain carrying both the fusion operon and the plasmid was exposed to a low concentration of MNNG, whereas the E. coli Ada protein encoded by a low-copy-number plasmid increased it about 40-fold under the same conditions. The low ability of AdaST to function as a positive regulator could account for the apparent lack of an adaptive response to alkylation damage in S. typhimurium.

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Section: Methodsmentioning

confidence: 99%

Cloning and characterization of the Salmonella typhimurium ada gene, which encodes O6-methylguanine-DNA methyltransferase

et al. 1991

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“…Rat liver eliminates O6-alkylguanine from DNA more rapidly than any other rodent tissue. This removal is enhanced by chronic exposure to nitrosamines (16)(17)(18)(19) and during the proliferative response after partial hepatectomy (20,21). More detailed investigations utilizing separated hepatocytes and nonparenchymal cells (NPC) indicated that rapid and enhanced removal of 06-alkylguanine were properties of hepatocytes only (22).…”

mentioning

confidence: 99%

“…When rats were exposed to diethynitrosamine (DEN) in the drinking water at 40 ppm, a regimen exclusively inducing hepatocellular carcinomas, no 0 -ethylguanine could be detected in hepatocytes by fluorescence after separation of the DNA bases by HPLC (2). In addition to the reaction for which it is named, 06-methylguanine-DNA methyltransferase activity also catalyzes the removal of ethyl residues from the 06 position of guanine (21,28) …”

Section: Introductionmentioning

confidence: 99%

O4-ethyldeoxythymidine, but not O6-ethyldeoxyguanosine, accumulates in hepatocyte DNA of rats exposed continuously to diethylnitrosamine.

Swenberg¹,

Dyroff²,

Bedell³

et al. 1984

Proc. Natl. Acad. Sci. U.S.A.

142

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In previous investigations into the mechanisms responsible for cell specificity in hepatocarcinogenesis, we have demonstrated that 06-methylguanine accumulates in the DNA of nonparenchymal cells (NPC) but is efficiently removed from hepatocellular DNA. 06-Alkylguanine may, therefore, be an important promutagenic lesion responsible for the induction of hepatic angiosarcomas after exposure to methylating agents, but other promutagenic DNA alkylation products-i.e., 04-alkylthymine-may be responsible for the initiation of hepatocellular carcinomas. F-344 male rats were provided drinking water containing diethylnitrosamine (DEN) at 40 ppm for 0, 2, 4, 8, 16, 28, 49, or is the hepatocarcinogenic effect of chronically administered alkylating agents in rodents (14, 15). Rat liver eliminates O6-alkylguanine from DNA more rapidly than any other rodent tissue. This removal is enhanced by chronic exposure to nitrosamines (16)(17)(18)(19) and during the proliferative response after partial hepatectomy (20, 21). More detailed investigations utilizing separated hepatocytes and nonparenchymal cells (NPC) indicated that rapid and enhanced removal of 06-alkylguanine were properties of hepatocytes only (22). Furthermore, these studies showed that 06-methylguanine accumulated in NPC during multiple or continuous exposure to either dimethylhydrazine (23-25) or dimethylnitrosamine (26) and that a pronounced mitogenic response in NPC was associated with exposure (26,27). Under exposure conditions leading to a high incidence of angiosarcomas, considerable amounts of promutagenic lesions thus accumulated in the DNA of replicating NPC. Contrary to NPC, hepatocytes removed 06-methylguanine with increasing efficiency as exposure continued such that the highest concentration of o methylguanine was detected in DNA after 1 day, but only 1/25th of this value was found after 2-4 weeks of exposure (23). When rats were exposed to diethynitrosamine (DEN) in the drinking water at 40 ppm, a regimen exclusively inducing hepatocellular carcinomas, no 0 -ethylguanine could be detected in hepatocytes by fluorescence after separation of the DNA bases by HPLC (2). In addition to the reaction for which it is named, 06-methylguanine-DNA methyltransferase activity also catalyzes the removal of ethyl residues from the 06 position of guanine (21,28)

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“…The pro-mutagenic lesion [O 6 ]meG can be removed by a cellular DNA repair enzyme, [O^alkylguanine-DNA alkyltransferase (53). The alkyltransferase has been demonstrated in Escherichia colt (54) and in numerous animal and human tissues (44); it has been shown that the hepatic enzyme system in rats is inducible by partial hepatectomy, hepatotoxic agents, and X-irradiation (55,56,57) i.e., under conditions of liver regeneration. Dietary nafenopin led to a significantly lower [O^meG/T-meG ratio in hepatic DNA (Table II).…”

Section: Discussionmentioning

confidence: 99%

Nafenopin-induced rat liver peroxisome proliferation reduces DNA methylation by N-nitrosodimethylamine in vivo

Wiestler¹,

Schmerold

Fringes

et al. 1985

Carcinogenesis

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Effect of partial hepatectomy on removal of O6-methylguanine from alkylated DNA by rat liver extracts

Cited by 71 publications

References 32 publications

Cloning and characterization of the Salmonella typhimurium ada gene, which encodes O6-methylguanine-DNA methyltransferase

Cloning and characterization of the Salmonella typhimurium ada gene, which encodes O6-methylguanine-DNA methyltransferase

O4-ethyldeoxythymidine, but not O6-ethyldeoxyguanosine, accumulates in hepatocyte DNA of rats exposed continuously to diethylnitrosamine.

Nafenopin-induced rat liver peroxisome proliferation reduces DNA methylation by N-nitrosodimethylamine in vivo

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