Artificial Intelligence uncovers carcinogenic human metabolites

ABSTRACT The genome of a eukaryotic cell is often vulnerable to both intrinsic and extrinsic threats due to its constant exposure to a myriad of heterogeneous compounds. Despite the availability of innate DNA damage response pathways, some genomic lesions trigger cells for malignant transformation. Accurate prediction of carcinogens is an ever-challenging task due to the limited information about bona fide (non)carcinogens. We developed Metabokiller, an ensemble classifier that accurately recognizes carcinogens by quantitatively assessing their electrophilicity as well as their potential to induce proliferation, oxidative stress, genomic instability, alterations in the epigenome, and anti-apoptotic response. Concomitant with the carcinogenicity prediction, Metabokiller is fully interpretable since it reveals the contribution of the aforementioned biochemical properties in imparting carcinogenicity. Metabokiller outperforms existing best-practice methods for carcinogenicity prediction. We used Metabokiller to unravel cells’ endogenous metabolic threats by screening a large pool of human metabolites and predicted a subset of these metabolites that could potentially trigger malignancy in normal cells. To cross-validate Metabokiller predictions, we performed a range of functional assays using Saccharomyces cerevisiae and human cells with two Metabokiller-flagged human metabolites namely 4-Nitrocatechol and 3,4-Dihydroxyphenylacetic acid and observed high synergy between Metabokiller predictions and experimental validations.