Gerona, R. R. | Search bioRxiv

bioRxiv2019

Drug resistant gut bacteria mimic a host mechanism for anticancer drug clearance

Pharmaceuticals are the top predictor of inter-individual variations in gut microbial community structure1, consistent with in vitro evidence that host-targeted drugs inhibit gut bacterial growth2 and are extensively metabolized by the gut microbiome3,4. In oncology, bacterial metabolism has been implicated in both drug efficacy5,6 and toxicity7,8; however, the degree to which bacterial drug sensitivity and metabolism can be driven by conserved pathways also found in mammalian cells remains poorly understood. Here, we show that anticancer fluoropyrimidine drugs inhibit the growth of diverse gut bacterial strains by disrupting pyrimidine metabolism, as in mammalian cells. Select bacteria metabolized 5-fluorouracil (5-FU) to its inactive metabolite dihydrofluorouracil (DHFU), mimicking the major host pathway for drug clearance. The preTA operon was necessary and sufficient for 5-FU inactivation in Escherichia coli, exhibited high catalytic efficiency for the reductive reaction, decreased the bioavailability and efficacy of oral fluoropyrimidine treatment in mice, and was prevalent in the gut microbiomes of colorectal cancer patients prior to and during treatment. The observed conservation of both the targets and pathways for metabolism of therapeutics across domains highlights the need to distinguish the relative contributions of human and microbial cells to drug disposition9, efficacy, and side effect profiles.

microbiology↗

bioRxiv2019

Integrating exposure knowledge and serum suspect screening as a new approach to biomonitoring: An application in firefighters and office workers

BackgroundWomen firefighters are exposed to recognized and probable carcinogens, yet there are few studies of chemical exposures and associated health concerns, such as breast cancer. Biomonitoring often requires a priori selection of compounds to be measured, and so may not detect important, lesser known, exposures.\n\nObjectivesThe Women Firefighters Biomonitoring Collaborative (WFBC) created a biological sample archive and conducted a general suspect screen (GSS) to address this data gap.\n\nMethodsUsing liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF/MS) we sought to identify candidate chemicals of interest in serum samples from 83 women firefighters (FF) and 79 office workers (OW) in San Francisco. Through the GSS approach we identified chemical peaks by matching accurate mass from serum samples against a custom chemical database of 740 slightly polar phenolic and acidic compounds, including many of relevance to firefighting or breast cancer etiology. We then selected chemicals for confirmation based on a priori criteria: 1) detection frequency or peak area differences between OW and FF; 2) evidence of mammary carcinogenicity, estrogenicity, or genotoxicity; and 3) not currently measured in large biomonitoring studies.\n\nResultsWe detected 620 chemicals that matched 300 molecular formulas in the WFBC database, including phthalate metabolites, phosphate flame retardant metabolites, phenols, pesticides, nitro-and nitroso-compounds, and per- and polyfluoroalkyl substances. The average number of chemicals from the database that were detected in participants was 72 and 70 in FF and OW, respectively. We confirmed 8 of the 20 prioritized suspect chemicals -including two alkylphenols, ethyl paraben, BPF, PFOSAA, benzophenone-3, benzyl p-hydroxybenzoate, and triphenyl phosphate--by running a matrix spike of the reference standards and using m/z, retention time and the confirmation of at least two fragment ions as criteria for matching.\n\nConclusionGSS provides a powerful high-throughput approach to identify and prioritize novel chemicals for biomonitoring and health studies.

epidemiology↗