Metabolism of dimethylnitrosamine and subsequent removal of O6-methylguanine from DNA by isolated rat hepatocytes

Diane R. Umbenhauer; Anthony E. Pegg

doi:10.1016/0009-2797(81)90043-0

Metabolism of dimethylnitrosamine and subsequent removal of O⁶-methylguanine from DNA by isolated rat hepatocytes

Diane R. Umbenhauer, Anthony E. Pegg

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Abstract

Freshly prepared isolated hepatocytes were shown to metabolize dimethylnitrosamine producing an alkylating agent which reacted with cellular DNA giving rise to 7-methylguanine and O⁶-methylguanine. Alkylation of DNA was prevented by aminoacetonitrile and was proportional to the dimethylnitrosamine concentration over the range of 1-90 μM. Isolated hepatocytes were able to catalyze the removal of O⁶-methylguanine from their DNA. After formation of this product by reaction with N-methyl-N-nitrosourea or dimethylnitrosamine to give extents of alkylation in the range of 0.1-15.0 μmol O⁶-methylguanine per mole of guanine in DNA, the loss produced in 3 h incubation was comparable to that seen in vivo from liver DNA alkylated to the same extent. The isolated hepatocytes therefore, provide a useful system in which factors influencing O⁶-methylguanine persistence in DNA can be studied.

Original language	English (US)
Pages (from-to)	229-238
Number of pages	10
Journal	Chemico-Biological Interactions
Volume	33
Issue number	2-3
DOIs	https://doi.org/10.1016/0009-2797(81)90043-0
State	Published - Jan 1981

All Science Journal Classification (ASJC) codes

Toxicology

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10.1016/0009-2797(81)90043-0

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@article{615e903286524379944404c00d2cdba2,

title = "Metabolism of dimethylnitrosamine and subsequent removal of O6-methylguanine from DNA by isolated rat hepatocytes",

abstract = "Freshly prepared isolated hepatocytes were shown to metabolize dimethylnitrosamine producing an alkylating agent which reacted with cellular DNA giving rise to 7-methylguanine and O6-methylguanine. Alkylation of DNA was prevented by aminoacetonitrile and was proportional to the dimethylnitrosamine concentration over the range of 1-90 μM. Isolated hepatocytes were able to catalyze the removal of O6-methylguanine from their DNA. After formation of this product by reaction with N-methyl-N-nitrosourea or dimethylnitrosamine to give extents of alkylation in the range of 0.1-15.0 μmol O6-methylguanine per mole of guanine in DNA, the loss produced in 3 h incubation was comparable to that seen in vivo from liver DNA alkylated to the same extent. The isolated hepatocytes therefore, provide a useful system in which factors influencing O6-methylguanine persistence in DNA can be studied.",

author = "Umbenhauer, {Diane R.} and Pegg, {Anthony E.}",

note = "Funding Information: The research was supported by grants CA 18137 and 1P 30 CA18450 from NCI, DHEW.",

year = "1981",

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doi = "10.1016/0009-2797(81)90043-0",

language = "English (US)",

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journal = "Chemico-Biological Interactions",

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T1 - Metabolism of dimethylnitrosamine and subsequent removal of O6-methylguanine from DNA by isolated rat hepatocytes

AU - Umbenhauer, Diane R.

AU - Pegg, Anthony E.

N1 - Funding Information: The research was supported by grants CA 18137 and 1P 30 CA18450 from NCI, DHEW.

PY - 1981/1

Y1 - 1981/1

N2 - Freshly prepared isolated hepatocytes were shown to metabolize dimethylnitrosamine producing an alkylating agent which reacted with cellular DNA giving rise to 7-methylguanine and O6-methylguanine. Alkylation of DNA was prevented by aminoacetonitrile and was proportional to the dimethylnitrosamine concentration over the range of 1-90 μM. Isolated hepatocytes were able to catalyze the removal of O6-methylguanine from their DNA. After formation of this product by reaction with N-methyl-N-nitrosourea or dimethylnitrosamine to give extents of alkylation in the range of 0.1-15.0 μmol O6-methylguanine per mole of guanine in DNA, the loss produced in 3 h incubation was comparable to that seen in vivo from liver DNA alkylated to the same extent. The isolated hepatocytes therefore, provide a useful system in which factors influencing O6-methylguanine persistence in DNA can be studied.

AB - Freshly prepared isolated hepatocytes were shown to metabolize dimethylnitrosamine producing an alkylating agent which reacted with cellular DNA giving rise to 7-methylguanine and O6-methylguanine. Alkylation of DNA was prevented by aminoacetonitrile and was proportional to the dimethylnitrosamine concentration over the range of 1-90 μM. Isolated hepatocytes were able to catalyze the removal of O6-methylguanine from their DNA. After formation of this product by reaction with N-methyl-N-nitrosourea or dimethylnitrosamine to give extents of alkylation in the range of 0.1-15.0 μmol O6-methylguanine per mole of guanine in DNA, the loss produced in 3 h incubation was comparable to that seen in vivo from liver DNA alkylated to the same extent. The isolated hepatocytes therefore, provide a useful system in which factors influencing O6-methylguanine persistence in DNA can be studied.

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ER -

Metabolism of dimethylnitrosamine and subsequent removal of O⁶-methylguanine from DNA by isolated rat hepatocytes

Abstract

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