Modeling the effect of phase II conjugations on topoisomerase I poisoning: pilot study with luteolin and quercetin.

Topoisomerases are targeted by several drugs in cancer chemotherapy acting as key enzymes in cell viability. Some flavonoids and their glycosides may exert health protective effects through the poisoning of topoisomerases. However, previous studies did not consider the substantial modifications taking place after ingestion neglecting that only metabolites can interact with the internal compartments of the human body. Since the high number of possible metabolites hinders their systematic analysis, an in silico approach can be a valuable tool to prioritize compounds by identifying candidates for further characterization. Specifically focusing on luteolin and quercetin, among the most ubiquitous flavonoids in the human diet, this work reports a computational procedure to model the effect of hepatic phase II conjugative metabolism on poisoning of human Topoisomerase I. As a general effect, glucuronidation and sulphation might enhance and quench poisoning activity, respectively. Among all, quercetin-3-O-glucuronide represents a promising candidate to be analyzed more thoroughly.