Model links contaminants from drug-making process to potential DNA damage

A model using yeast suggests that contaminants created during the drug manufacturing process may damage DNA. N-nitrosamines and related compounds can be formed during the manufacture of a medication via reactions between nitrates or nitrites and certain amines. They also commonly occur in processed meats, alcoholic beverages, cosmetics, and cigarette smoke. Generally, very small levels are not believed to present a risk but there are a lot of unknowns, exposure can vary widely, and little is understood about low-level long-term exposure, according to Ogbede et al from the University of British Columbia in Nature Scientific Reports. “Although our bodies are exposed to thousands of diverse chemical toxins, our understanding of their mechanisms of action is limited,” they wrote. However, there was an international recall of sartan-type drugs in 2018 after contamination with N-nitrosodimethylamine (NDMA), a genotoxic and carcinogenic toxin, was detected. N-nitrosodiethylamine (NDEA) and N-methyl-N-aminobutyric acid (NMBA) were found in various lots of the drugs from several manufacturers. The contaminants were initially detected in the active pharmaceutical ingredients, and resulted from the solvents used in their production and drug breakdown during storage. Since then, there have been additional recalls of other drug classes including metformin and ranitidine due to unacceptably high levels of NDMA. Yet “our understanding of how these toxins exert their biological effects on cellular systems is limited,” the authors said. To address this, the researchers used a validated yeast chemogenomic platform to characterize the effects of several of the contaminants on 4,800 yeast strains. They studied three N-nitrosamines (NDMA, NDEA and NMBA), two related compounds, and several of their metabolites including methylamine, ethylamine, formamide, formaldehyde and ammonium sulfate. It was found the contaminants had significant effects on DNA repair, the machinery that makes cell proteins and on cell mitochondria. The researchers developed a publicly-available database to help elucidate what sort of risks the contaminants may present. The interactive chemogenomic web application shows genes which are sensitive to exposure and genetic pathways, meaningful to scientific users. They noted the model may not apply directly to multi-celled organisms. “This comprehensive dataset of deletion strains that are affected by exposure to N-nitrosamines and related compounds, combined with an accessible, queryable database represents a valuable resource that can provide new insights and inspire further work into the biological consequences of exposure to these contaminants. SOURCES: 1. https://www.nature.com/articles/s41598-021-91792-1 2. https://news.ubc.ca/2021/06/15/new-study-finds-contaminants-in-many-generic-drugs-may-have-harmful-effects/?utm_medium=email&utm_campaign=Catalyst---June-2021&utm_source=Envoke-Catalyst&utm_term=Catalyst%3A-June-2021

Model links contaminants from drug-making process to potential DNA damage

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