2-Hydroxypyridine-N-oxide (HOPO): Equivocal in the ames assay

Environmental and Molecular Mutagenesis
Krista DoboMichelle Kenyon

Abstract

2-Hydroxypyridine-N-oxide (HOPO) is a useful coupling reagent for synthesis of active pharmaceutical ingredients. It has been reported to be weakly mutagenic in the Ames assay (Ding W et al. []: J Chromatogr A 1386:47-52). According to the ICH M7 guidance (2014) regarding control of mutagenic impurities to limit potential carcinogenic risk, mutagens require control in drug substances such that exposure not exceeds the threshold of toxicological concern. Given the weak response observed in the Ames assay and the lack of any obvious structural features that could confer DNA reactivity we were interested to determine if the results were reproducible and investigate the role of potentially confounding experimental parameters. Specifically, Ames tests were conducted to assess the influence of compound purity, solvent choice, dose spacing, toxicity, type of S9 (aroclor vs phenobarbital/β-napthoflavone), and lot variability on the frequency of HOPO induced revertant colonies. Initial extensive testing using one lot of HOPO produced no evidence of mutagenic potential in the Ames assays. Subsequent studies with four additional lots produced conflicting results, with an ∼2.0-fold increase in revertant colonies observed. Given the rigor o...Continue Reading

References

Jan 1, 1985·Environmental Mutagenesis·E R NestmannT R Harrington
Aug 1, 1973·Proceedings of the National Academy of Sciences of the United States of America·B N AmesF D Lee
May 1, 1983·Mutation Research·D M Maron, B N Ames
Dec 13, 2000·Mutation Research·K Mortelmans, E Zeiger
Mar 24, 2007·Regulatory Toxicology and Pharmacology : RTP·Michelle O KenyonWarren W Ku
Jan 27, 2009·Chemical Society Reviews·Eric Valeur, Mark Bradley
Dec 30, 2014·Regulatory Toxicology and Pharmacology : RTP·Alexander P HardingMichael Kranz
Oct 25, 2017·Regulatory Toxicology and Pharmacology : RTP·William C GuntherKrista L Dobo

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Citations

Apr 20, 2019·Environmental and Molecular Mutagenesis·Krista L DoboMichael Homiski

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