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Pyrroxamide, a nonionic nitroxyl spin label contrast agent for magnetic resonance imaging. Mutagenesis and cell
D G Gordon1, R C Brasch, M D Ogan
1Department of Radiology, University of California, San Francisco 94143-0628.
Abstract:
Pyrroxamide [N-(1-hydroxymethyl-2,3-dihydroxypropyl)-2,2,5,5-tetramethyl pyrrolidine-1-oxyl-3-carboxyamide] is a newly tested nonionic monomeric nitroxyl compound with demonstrated effectiveness for MRI contrast enhancement at doses as low as 10(-3) M. Pyrroxamide and its hydroxylamine metabolic derivative were tested in concentrations from 10(-9) to 10(-2) M with a battery of cytotoxic and mutagenic assays using mammalian Chinese hamster ovary cells. Loci-specific mutation induction was examined at the hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and the Na+/K+ ATPase loci, both in the presence and absence of a liver microsomal metabolic activating mixture (S-9 mix). Cell survival and induction of sister chromatid exchanges also were studied. All tests yielded negative results indicating that pyrroxamide and and hydroxylamine derivative were both noncytotoxic and nonmutagenic at the doses tested.
Insights
Pyrroxamide, a novel MRI contrast agent, was evaluated for safety. Studies confirmed pyrroxamide and its metabolite are non-cytotoxic and non-mutagenic in mammalian cells at tested concentrations.
Area of Science:
- Biochemistry
- Toxicology
- Medical Imaging
Background:
- Pyrroxamide is a new nonionic monomeric nitroxyl compound.
- It shows promise as an effective MRI contrast agent, even at low concentrations (10^-3 M).
Purpose of the Study:
- To assess the cytotoxic and mutagenic potential of pyrroxamide and its hydroxylamine derivative.
- To evaluate safety for potential use in medical imaging.
Main Methods:
- Mammalian Chinese hamster ovary cells were used for testing.
- Cytotoxicity and mutagenicity assays were performed across a concentration range (10^-9 to 10^-2 M).
- Specific gene loci (HGPRT, Na+/K+ ATPase) and sister chromatid exchanges were examined, with and without metabolic activation (S-9 mix).
Main Results:
- All cytotoxic and mutagenic assays yielded negative results.
- Pyrroxamide demonstrated no significant impact on cell survival.
- No induction of mutations or sister chromatid exchanges was observed.
Conclusions:
- Pyrroxamide and its hydroxylamine derivative are non-cytotoxic.
- Pyrroxamide and its hydroxylamine derivative are non-mutagenic at the tested doses.
- These findings support the safety profile of pyrroxamide for potential MRI applications.