PMID: 2499776Jun 1, 1989Paper

Importance of multiple hydroxylated metabolites in hexamethylphosphoramide (HMPA)-mediated mutagenesis in Drosophila melanogaster

Mutation Research
J A ZijlstraE W Vogel

Abstract

The mutagenic profiles in Drosophila and the influence of inhibition of metabolism on genotoxic activity were determined for hexamethylphosphoric triamide (HMPA), some synthetically prepared presumed metabolites and ethylated analogs. Demethylated HMPA metabolites are considerably less mutagenic than HMPA, dependent on the degree of demethylation. The mutagenicity of the presumptive primary metabolite, hydroxymethyl pentamethylphosphoramide (HM-Me5-PA), is comparable to HMPA and can be decreased considerably by inhibition of the metabolism by 1-phenylimidazole or iproniazid. This suggests that further oxidative metabolism is required for mutagenic activity. The mutagenicity of the doubly hydroxylated HMPA metabolite, N,N'-bis(hydroxymethyl)-tetramethylphosphoramide (N,N'-(HM)2-Me4-PA) can also be decreased by inhibition of metabolism, whereas the 3-fold hydroxylated N,N',-N"-(HM)3-Me3-PA is not affected by pretreatment with enzyme inhibitors, indicating that no further oxidative metabolism is required for its activation. A second hydroxylation on 1 dimethylamino group, forming N,N-(HM)2-Me4-PA, results in a drastic loss of mutagenic activity. Further oxidation of HM-Me5-PA to formyl pentamethylphosphoramide (formyl-Me5-PA) also...Continue Reading

References

Dec 15, 1977·Biochemical Pharmacology·C J Rutty, T A Connors
Jul 1, 1976·Mutation Research·R J Wilkins, H D Macleod
Mar 1, 1988·Mutation Research·J A Zijlstra, E W Vogel
Jul 1, 1970·Journal of Medicinal Chemistry·P H Terry, A B Borkovec
Nov 21, 1967·Biochimica Et Biophysica Acta·M Y Feldman
Nov 1, 1968·Biochemical Pharmacology·A R Jones, H Jackson
Mar 1, 1984·Chemico-biological Interactions·J A ZijlstraD D Breimer
Feb 1, 1980·Chemico-biological Interactions·C J Rutty, G Abel
Jan 15, 1981·Biochemical and Biophysical Research Communications·K K AnderssonP Maurel
Jan 1, 1982·Pharmacology·D M Chambers, G C Jefferson

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Citations

Aug 1, 1995·Mutation Research·E W Vogel, A T Natarajan
Dec 31, 1997·Mutation Research·M S BogdanffyA E Harman
Jun 21, 2016·The Journal of Organic Chemistry·Chriss E McDonaldJustin A Cumens
Jan 1, 1993·Environmental and Molecular Mutagenesis·E W VogelM J Nivard
Oct 29, 2010·Organic Letters·Chriss E McDonaldMichael R Cecchini
Jul 1, 2020·Organic Letters·Chriss E McDonaldAngelique T Delgado

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