DNA alkyation and mutagenicity of related hydroxypropylating and methylating agents in V79 cells

Terence A Lawson, Peter Gannett

Research output: Contribution to journalArticle

Abstract

N‐Nitrosobis (2‐hydroxypropyl) amine (BHP) and N‐nitrosobis (2‐oxopropyl) amine (BOP) require metabolism to be carcinogenic and mutagenic. This metabolism produces hydroxypropylating and methylating alkylating species. To measure the effects of these species, we compared the action of direct‐acting model compounds that are hydroxypropylating or methylating agents with those of BHP and BOP. Mutagenicity in V79 cells and the alkylation of V79 cell DNA were measured. The model compounds were ethyl‐N‐nitroso (2‐oxopropyl) carbamate (NOPC), a methylating agent, and its 2‐hydroxypropyl congener (NHPC), a hydroxypropylating agent. BHP and BOP were metabolized by hepatocytes from male Syrian hamsters. At the highest dose (2 mM) BOP produced 12 times more mutants than BHP but only 2.5 times more O6methylguanine (O6MeG) than BHP. When a pancreas duct homogenate was used, 87 (BOP) and six (BHP) mutants/106 survivors were measured. When hepatocytes (not a homogenate) were used to metabolize BOP, 351 μmol O6MeG/mol guanine (G) and 39 μmol O6 (2‐hydroxypropyl) G (O6HpG)/mole G were found in V79 DNA. When a pancreas duct homogenate was used BHP produced O6HpG (65 μmol/mol G) and BOP O6MeG (20 μmol/mol G). NOPC produced five times more mutants than NHPC, over the range of doses. At the highest dose (10 μM) it produced less (70%) O6alkylG than NHPC. These data show that methylation was a more mutagenic lesion than hydroxypropylation. There was no evidence of a correlation between mutagenicity and the formation of O6alkylG. ©1993 Wiley‐Liss, Inc.

Original languageEnglish (US)
Pages (from-to)269-275
Number of pages7
JournalTeratogenesis, Carcinogenesis, and Mutagenesis
Volume13
Issue number6
DOIs
StatePublished - Jan 1 1993

Fingerprint

Amines
Pancreas
Hepatocytes
Metabolism
Ducts
Carbamates
DNA
Mesocricetus
Guanine
Alkylation
Methylation

Keywords

  • Omethylguanine
  • V79 cells
  • alkylation
  • methylation
  • mutagenicity
  • nitrosamines

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Genetics
  • Genetics(clinical)
  • Health, Toxicology and Mutagenesis

Cite this

DNA alkyation and mutagenicity of related hydroxypropylating and methylating agents in V79 cells. / Lawson, Terence A; Gannett, Peter.

In: Teratogenesis, Carcinogenesis, and Mutagenesis, Vol. 13, No. 6, 01.01.1993, p. 269-275.

Research output: Contribution to journalArticle

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abstract = "N‐Nitrosobis (2‐hydroxypropyl) amine (BHP) and N‐nitrosobis (2‐oxopropyl) amine (BOP) require metabolism to be carcinogenic and mutagenic. This metabolism produces hydroxypropylating and methylating alkylating species. To measure the effects of these species, we compared the action of direct‐acting model compounds that are hydroxypropylating or methylating agents with those of BHP and BOP. Mutagenicity in V79 cells and the alkylation of V79 cell DNA were measured. The model compounds were ethyl‐N‐nitroso (2‐oxopropyl) carbamate (NOPC), a methylating agent, and its 2‐hydroxypropyl congener (NHPC), a hydroxypropylating agent. BHP and BOP were metabolized by hepatocytes from male Syrian hamsters. At the highest dose (2 mM) BOP produced 12 times more mutants than BHP but only 2.5 times more O6methylguanine (O6MeG) than BHP. When a pancreas duct homogenate was used, 87 (BOP) and six (BHP) mutants/106 survivors were measured. When hepatocytes (not a homogenate) were used to metabolize BOP, 351 μmol O6MeG/mol guanine (G) and 39 μmol O6 (2‐hydroxypropyl) G (O6HpG)/mole G were found in V79 DNA. When a pancreas duct homogenate was used BHP produced O6HpG (65 μmol/mol G) and BOP O6MeG (20 μmol/mol G). NOPC produced five times more mutants than NHPC, over the range of doses. At the highest dose (10 μM) it produced less (70{\%}) O6alkylG than NHPC. These data show that methylation was a more mutagenic lesion than hydroxypropylation. There was no evidence of a correlation between mutagenicity and the formation of O6alkylG. {\circledC}1993 Wiley‐Liss, Inc.",
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AB - N‐Nitrosobis (2‐hydroxypropyl) amine (BHP) and N‐nitrosobis (2‐oxopropyl) amine (BOP) require metabolism to be carcinogenic and mutagenic. This metabolism produces hydroxypropylating and methylating alkylating species. To measure the effects of these species, we compared the action of direct‐acting model compounds that are hydroxypropylating or methylating agents with those of BHP and BOP. Mutagenicity in V79 cells and the alkylation of V79 cell DNA were measured. The model compounds were ethyl‐N‐nitroso (2‐oxopropyl) carbamate (NOPC), a methylating agent, and its 2‐hydroxypropyl congener (NHPC), a hydroxypropylating agent. BHP and BOP were metabolized by hepatocytes from male Syrian hamsters. At the highest dose (2 mM) BOP produced 12 times more mutants than BHP but only 2.5 times more O6methylguanine (O6MeG) than BHP. When a pancreas duct homogenate was used, 87 (BOP) and six (BHP) mutants/106 survivors were measured. When hepatocytes (not a homogenate) were used to metabolize BOP, 351 μmol O6MeG/mol guanine (G) and 39 μmol O6 (2‐hydroxypropyl) G (O6HpG)/mole G were found in V79 DNA. When a pancreas duct homogenate was used BHP produced O6HpG (65 μmol/mol G) and BOP O6MeG (20 μmol/mol G). NOPC produced five times more mutants than NHPC, over the range of doses. At the highest dose (10 μM) it produced less (70%) O6alkylG than NHPC. These data show that methylation was a more mutagenic lesion than hydroxypropylation. There was no evidence of a correlation between mutagenicity and the formation of O6alkylG. ©1993 Wiley‐Liss, Inc.

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