TY - JOUR
T1 - Metabolism of O6-alkyldeoxyguanosines and their effect on removal of O6-methylguanine from rat liver DNA
AU - Pegg, Anthony
AU - Swann, Peter F.
N1 - Funding Information:
This researchw as supportedb y grants CA18137 and 1P30 CA18450 and contract CP61063 awarded by the National Cancer Institute, U.S. Public
PY - 1979/12/17
Y1 - 1979/12/17
N2 - O6-Methyldeoxyguanosine and O6-ethyldeoxyguanosine are weak inhibitors (of approximately equal potency) of the removal of O6-methylguanine from methylated DNA by a rat liver enzyme in vitro. When administered to rats, O6-ethyldeoxyguanosine retarded the removal from liver DNA of the O6-methylguanine which had been produced by pretreatment with dimethylnitrosamine, but the effect was short lived. O6-Methyldeoxyguanosine was much less effective. When cells in culture were grown in a medium containing radioactive O6-methylguanine or O6-methyldeoxyguanosine there was negligible incorporation of the methylated base into DNA, but substantial conversion to guanine which was incorporated. When these substances were injected into rats after partial hepatectomy, a very small incorporation of O6-methylguanine into DNA apparently occurred. Both O6-ethyldeoxyguanosine and O6-methyldeoxyguanosine were dealkylated by rat liver extracts, but the methylated derivative was metabolized much more rapidly. O6-Methylguanosine and O6-ethylguanosine were also dealkylated by rat liver extracts, but the corresponding bases were not attacked. This reaction was probably carried out by the adenosine deaminase in the extracts because it could be prevented by addition of erythro-9-(2-hydroxy-3-nonyl)adenine, a potent adenosine deaminase inhibitor, and could also be effected by purified calf intestinal adenosine deaminase. The Km for the demethylation of O6-methyldeoxyguanosine by calf intestinal adenosine deaminase was comparable to that for adenosine, whereas the Km for O6-ethyldeoxyguanosine was ten times greater. The V for O6-methyldeoxyguanosine was about 11% that for adenosine, but that for O6-ethyldeoxyguanosine was only 0.3%. The higher Km and the slower V for O6-ethyldeoxyguanosine may contribute to the slower dealkylation of this nucleoside by liver extracts and could account for its greater effect on slowing O6-methylguanine excision from DNA in vivo.
AB - O6-Methyldeoxyguanosine and O6-ethyldeoxyguanosine are weak inhibitors (of approximately equal potency) of the removal of O6-methylguanine from methylated DNA by a rat liver enzyme in vitro. When administered to rats, O6-ethyldeoxyguanosine retarded the removal from liver DNA of the O6-methylguanine which had been produced by pretreatment with dimethylnitrosamine, but the effect was short lived. O6-Methyldeoxyguanosine was much less effective. When cells in culture were grown in a medium containing radioactive O6-methylguanine or O6-methyldeoxyguanosine there was negligible incorporation of the methylated base into DNA, but substantial conversion to guanine which was incorporated. When these substances were injected into rats after partial hepatectomy, a very small incorporation of O6-methylguanine into DNA apparently occurred. Both O6-ethyldeoxyguanosine and O6-methyldeoxyguanosine were dealkylated by rat liver extracts, but the methylated derivative was metabolized much more rapidly. O6-Methylguanosine and O6-ethylguanosine were also dealkylated by rat liver extracts, but the corresponding bases were not attacked. This reaction was probably carried out by the adenosine deaminase in the extracts because it could be prevented by addition of erythro-9-(2-hydroxy-3-nonyl)adenine, a potent adenosine deaminase inhibitor, and could also be effected by purified calf intestinal adenosine deaminase. The Km for the demethylation of O6-methyldeoxyguanosine by calf intestinal adenosine deaminase was comparable to that for adenosine, whereas the Km for O6-ethyldeoxyguanosine was ten times greater. The V for O6-methyldeoxyguanosine was about 11% that for adenosine, but that for O6-ethyldeoxyguanosine was only 0.3%. The higher Km and the slower V for O6-ethyldeoxyguanosine may contribute to the slower dealkylation of this nucleoside by liver extracts and could account for its greater effect on slowing O6-methylguanine excision from DNA in vivo.
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U2 - 10.1016/0005-2787(79)90202-8
DO - 10.1016/0005-2787(79)90202-8
M3 - Article
C2 - 518880
AN - SCOPUS:0018794712
SN - 0005-2787
VL - 565
SP - 241
EP - 252
JO - BBA Section Nucleic Acids And Protein Synthesis
JF - BBA Section Nucleic Acids And Protein Synthesis
IS - 2
ER -