Oncogenicity by Methyl Methanesulfonate in Male RF Mice

Clapp, Neal K.; Craig, A. W.; Toya, R. E.

doi:10.1126/science.161.3844.913

Cited by 36 publications

(5 citation statements)

References 8 publications

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“…Methylating agents acting by an SN2 mechanism, that is, MMS and DMS, are carcinogens (Clapp et al, 1968;Swann and Magee, 1969;Kleihues et al, 1972;Druckrey et al, 1970). Consequently, SAM should also be a weak carcinogen, and perturbation of SAM metabolism might lead to an increased cancer frequency.…”

Section: Discussionmentioning

confidence: 99%

Nonenzymatic methylation of DNA by the intracellular methyl group donor S-adenosyl-L-methionine is a potentially mutagenic reaction.

Rydberg¹,

Lindahl²

1982

The EMBO Journal

381

236

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Incubation of DNA with S‐adenosyl‐L‐methionine (SAM) in neutral aqueous solution leads to base modification, with formation of small amounts of 7‐methylguanine and 3‐methyladenine. The products have been identified by high performance liquid chromatography of DNA hydrolysates and by the selective release of free 3‐methyladenine from SAM‐treated DNA by a specific DNA glycosylase. We conclude that SAM acts as a weak DNA‐alkylating agent. Several control experiments including extensive purification of [3H‐methyl]SAM preparations and elimination of the alkylating activity by pretreatment of SAM with a phage T3‐induced SAM cleaving enzyme, have been performed to determine that the activity observed was due to SAM itself and not to a contaminating substance. We estimate that SAM, at an intracellular concentration of 4 X 10(‐5) M, causes DNA alkylation at a level similar to that expected from continuous exposure of cells to 2 X 10(‐8) M methyl methane‐sulphonate. This ability of SAM to act as a methyl donor in a nonenzymatic reaction could result in a background of mutagenesis and carcinogenesis. The data provide an explanation for the apparently universal occurrence of multiple DNA repair enzymes specific for methylation damage.

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Section: Discussionmentioning

confidence: 99%

Nonenzymatic methylation of DNA by the intracellular methyl group donor S-adenosyl-L-methionine is a potentially mutagenic reaction.

Rydberg¹,

Lindahl²

1982

The EMBO Journal

381

236

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“…The agents chosen may be classified into two groups. The first, represented by dimethyl sulphate and methyl methanesulphonate, are considered as reacting mainly through the SN2 mechanism, and, in terms of biological action, can be classified as relatively weak carcinogens (Clapp et al, 1968;Druckrey et al, 1970;Frei, 1971;Swann & Magee, 1968). The second, represented by N-methyl-N-nitrosourea and N-methyl-N'-nitro-N-nitrosoguanidine, are regarded as reacting through generation of the methyldiazonium ion, and may be classified as SN1 agents.…”

mentioning

confidence: 99%

The molecular basis for biological inactivation of nucleic acids. The action of methylating agents on the ribonucleic acid-containing bacteriophage R17

Shooter

Howse

Shah

et al. 1974

Biochemical Journal

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1. The inactivation of an RNA-containing bacteriophage after reaction with four methylating agents was studied. Measurements of the extent of methylation of the RNA and of the nature and amounts of the various reaction products were made. In experiments with dimethyl sulphate and methyl methanesulphonate inactivation can be quantitatively accounted for by methylation at two of the positions involved in hydrogen bonding: N-1 of adenine and N-3 of cytosine. In experiments with N-methyl-N-nitrosourea and N-methyl-N'-nitro-N-nitrosoguanidine methylation at N-1 of adenine and N-3 of cytosine accounts for only about one-half of the observed inactivation. Scission of the RNA chain during reaction accounts for a further 20% of the inactivation. To account for the remainder it seems necessary to postulate that formation of O(6)-methylguanine constitutes a lethal lesion. 2. Breaks in the RNA chain formed on reaction with the nitroso derivatives presumably result from methylation of the phosphate diester group followed by hydrolysis of the unstable triester thus formed.

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“…[More detailed information is shown in Table 3. ] Whether or not the mutagenic activity of alkyl sulfonates translates into a carcinogenic response is by no means clear in that only MMS has been subjected to anything approaching an acceptable standard rodent carcinogenicity bioassay (Clapp et al 14 ) involving administration via drinking water in male mice. MMS is reported to possess only moderate carcinogenic potency (TD 50 = 31.8 mg/kg/day, 15 as discussed below).…”

Section: Toxicological Aspects: Mutagenic Activitymentioning

confidence: 99%

Mutagenic Alkyl-Sulfonate Impurities in Sulfonic Acid Salts: Reviewing the Evidence and Challenging Regulatory Perceptions

Snodin¹,

Teasdale

2015

Org. Process Res. Dev.

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Alkyl sulfonates are direct-acting bacterial mutagens and are almost universally regarded by regulatory authorities to be potential impurities in drug substances presented as sulfonic acid salts, particularly if synthesized using an alcohol solvent. A detailed review of the available public domain data indicates that regulatory policy appears to be based on speculation, assumption, and assertion rather than actual evidence. Ester formation from a sulfonic acid in the presence of an alcohol is an extremely slow and thermodynamically unfavored reaction requiring strongly acidic conditions to produce even minimal conversion. Following addition of an equimolar amount of a sulfonic acid to a pharmaceutical base (the active), proton transfer to form an acid salt occurs instantaneously, thus neutralizing the acid and precluding any ester formation as a side reaction even if an alcoholic solvent is employed. Other possible routes to sulfonic acid ester formation by interaction of an alcohol with preformed sulfonic acid salt or via impurities in the sulfonic acid reagent can also be discounted based on mechanistic and experimental evidence. By contrast, C 1 −C 3 chloroalkanes are formed more rapidly in HCl/alcohol systems, but they can be readily purged from hydrochloride salts (if an excess of acid is used for synthesis) and are much weaker biological alkylators than alkyl sulfonates. Generic/compound-specific limits for alkyl sulfonates and considerably higher limits for chloroalkanes can be derived using the available toxicological data and provisions of the International Conference on Harmonization (ICH) M7 guideline. Since alkyl-sulfonate impurities can now be predicted with certainty to be absent at toxicologically significant levels, the current regulatory paradigm is no longer considered to be justified, thus removing the hypothetically based perception of potential risk associated with sulfonic acid salts.

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Oncogenicity by Methyl Methanesulfonate in Male RF Mice

Cited by 36 publications

References 8 publications

Nonenzymatic methylation of DNA by the intracellular methyl group donor S-adenosyl-L-methionine is a potentially mutagenic reaction.

Nonenzymatic methylation of DNA by the intracellular methyl group donor S-adenosyl-L-methionine is a potentially mutagenic reaction.

The molecular basis for biological inactivation of nucleic acids. The action of methylating agents on the ribonucleic acid-containing bacteriophage R17

Mutagenic Alkyl-Sulfonate Impurities in Sulfonic Acid Salts: Reviewing the Evidence and Challenging Regulatory Perceptions

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