Abstract
Caffeine (1, 3, 7-trimethylxanthine), an alkaloid produced by plants, has antioxidant and insecticide properties that can affect metabolism and cognition. In vertebrates, the metabolites derived from caffeine have been identified, and their functions have been characterized. However, the metabolites of caffeine in insects remain unknown. Thus, using radiolabelled caffeine, we have identified some of the primary caffeine metabolites produced in the body of Drosophila melanogaster males, including theobromine, paraxanthine and theophylline. In contrast to mammals, theobromine was the predominant metabolite (paraxanthine in humans; theophylline in monkeys; 1, 3, 7-trimethyluric acid in rodents). A transcriptomic screen of Drosophila flies exposed to caffeine revealed the coordinated variation of a large set of genes that encode xenobiotic-metabolizing proteins, including several cytochromes P450s (CYPs) that were highly overexpressed. Flies treated with metyrapone—an inhibitor of CYP enzymes—showed dramatically decreased caffeine metabolism, indicating that CYPs are involved in this process. Using interference RNA genetic silencing, we measured the metabolic and transcriptomic effect of three candidate CYPs. Silencing of CYP6d5 completely abolished theobromine synthesis, whereas CYP6a8 and CYP12d1 silencing induced different consequences on metabolism and gene expression. Therefore, we characterized several metabolic products and some enzymes potentially involved in the degradation of caffeine. In conclusion, this pioneer approach to caffeine metabolism in insects opens novel perspectives for the investigation of the physiological effects of caffeine metabolites. It also indicates that caffeine could be used as a biomarker to evaluate CYP phenotypes in Drosophila and other insects.
Highlights
Caffeine (1, 3, 7-trimethylxanthine) is a typical purine alkaloid that is produced in a variety of plants, including coffee (Coffea arabica) and tea (Camellia sinensis) [1]
The measure of caffeine metabolites in urine provides an accurate assessment of an individual’s ability to metabolize drugs [43]. This measure is often based on the activity of CYP1A2, one of the main human enzymes involved in caffeine metabolism
In cases of combined ingestion of caffeine with pharmaceutical compounds, the measurement of CYP1A2 activity allows for precise adjustment of the optimal drug amount required for each person [44,45]
Summary
Caffeine (1, 3, 7-trimethylxanthine) is a typical purine alkaloid that is produced in a variety of plants, including coffee (Coffea arabica) and tea (Camellia sinensis) [1]. Caffeine is involved in plant chemical defense, acting as a repellent, pesticide and allelopathic agent [2,3,4]. Caffeine Metabolism in Drosophila melanogaster collection and analysis, decision to publish, or preparation of the manuscript
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