Quantification of Raloxifene Specific 471 Da Adducts in CYP3A4 and P450-Reductase

ABSTRACT: Drugs are often metabolized to reactive intermediates that form protein adducts. Adducts can inhibit critical proteins, elicit immune responses, and cause life threatening adverse drug reactions. The masses of metabolites are frequently unknown, rendering traditional mass spectrometry-based proteomics approaches incapable of adduct identification: masses require defining before searching. “Open” search algorithms address this problem. Here, we present Magnum, an open search tool optimized for adduct identification; and Limelight, a web-based data processing package for analysis and visualization of data from all existing search algorithms, incorporating specific tools for sample comparisons and xenobiotic-adduct discovery. We demonstrate, using three drug/protein combinations, our new methods and software tools enable accurate identification of xenobiotic-protein adducts with no prior knowledge of adduct masses or protein targets. Magnum outperforms existing tools in xenobiotic-protein adduct discovery, while Limelight fulfills a major need in the rapidly developing field of open searching, which until now has had no comprehensive data visualization tools.

ORGANISM(S): Homo Sapiens Rattus Norvegicus

SUBMITTER: Alex Zelter  

PROVIDER: PXD024932 | panorama | Mon Feb 21 00:00:00 GMT 2022

REPOSITORIES: PanoramaPublic