The December 2019 Editor's Choice article is "In Vivo Mutagenicity Testing of Arylboronic Acids and Esters" (https://onlinelibrary.wiley.com/doi/10.1002/em.22320) by Melisa Masuda-Herrera, Krista Dobo, Michelle Kenyon, Julia Kenny, Sheila Galloway, Patricia Escobar, M. Vijayaraj Reddy, Robert Jolly, Alejandro Trejo-Martin, Caren Brown, Marie Mckean, Megan Young, Shannon Bruce, Kamala Pant, Aparajita Dutta, Rohan Kulkarni, and Joel Bercu.
Pharmaceutical companies must provide evidence to worldwide Health Authorities, such as the US Food and Drug Administration (FDA), that medicines are safe and efficacious for use in humans. A required part of safety testing is to evaluate whether a drug causes DNA damage, which could indicate an increased risk of cancer. Any impurities left over in the final drug as a result of chemicals used in making the drug are also evaluated for DNA-damaging potential. Arylboronic acids and esters, which are frequently used in making drugs, show mutagenic activity in the Ames test, which uses bacteria to detect whether a chemical causes an irreversible change, or mutation, in the genetic code. Therefore, this family of chemicals must be monitored as potential impurities and controlled to very low (parts per million) levels in drugs to avoid any risk of cancer. This adds to the complexity and expense of making drugs. Considering the usefulness of arylboronic compounds in making drugs efficiently, scientists from several pharmaceutical companies worked together (Masuda-Herrera et al., 2019) to learn whether the results of the bacterial Ames test truly indicate a risk of DNA damage when tested in animals.
An international agreement exists on appropriate ways to investigate the biological relevance of chemicals active in the bacterial mutation (Ames) test (International Conference on Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, Guideline ICH M7(R1); “Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk”). Following these recommendations, the scientists tested a variety of 8 arylboronic compounds (6 of which were mutagenic in bacteria) in animals using the Pig-a, micronucleus, and/or comet assays. The Pig-a and micronucleus assays detect mutagenic events (small DNA changes) and chromosome damage (larger DNA changes) in blood cells, and the comet assay detects DNA damage, which may or may not produce mutations, depending on whether the damage is repaired. To show that the cells tested were exposed, it was confirmed that the chemicals administered orally were present in the bloodstream. All the animal studies were negative. These findings demonstrate that the risk of mutagenicity from arylboronic compounds, present as impurities in drugs, may be low.
Environ Mol Mutagen 60: 766-777, 2019. © 2019 Wiley Periodicals, Inc.