Carbonyl reduction pathway in hepatic in vitro metabolism of anthracyclines: Impact of structure on biotransformation rate. (15th May 2021)

• Record Type: Journal Article
• Authors: Piska, Kamil; Jamrozik, Marek; Koczurkiewicz-Adamczyk, Paulina; Bucki, Adam; Żmudzki, Paweł; Kołaczkowski, Marcin; Pękala, Elżbieta
• Is Part Of: Toxicology letters. Volume 342(2021)
• Page Start: 50
• Page End: 57
• Publication Date: 2021-05-15
• Subjects: Anthracyclines -- Drug toxicity -- Pharmacokinetics -- Drug metabolism -- structure–metabolism relationship; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2021.02.001
• Languages: English
• ISSNs: 0378-4274

Abstract

Graphical abstract: Highlights: Anthracyclines metabolic rate depends on a presence of the side-chain hydroxy group. Side-chain hydroxy group affects the binding of anthracyclines with CBR1 active site. Side-chain hydroxy group influences partial atomic charge of a reactive oxygen atom. In silico methods may help predict anthracyclines metabolism rate. Abstract: Carbonyl reduction biotransformation pathway of anthracyclines (doxorubicin, daunorubicin) is a significant process, associated with drug metabolism and elimination. However, it also plays a pivotal role in anthracyclines-induced cardiotoxicity and cancer resistance. Herein, carbonyl reduction of eight anthracyclines, at in vivo relevant concentrations (20 μM), was studied in human liver cytosol, to describe the relationship between their structure and metabolism. Significant differences of intrinsic clearance between anthracyclines, ranging from 0, 62–74, 9 μL/min/mg were found and associated with data from in silico analyses, considering their binding in active sites of the main anthracyclines-reducing enzymes: carbonyl reductase 1 (CBR1) and aldo-keto reductase 1C3 (AKR1C3). Partial atomic charges of carbonyl oxygen atom were also determined and considered as a factor associated with reaction rate. Structural features, including presence or absence of side-chain hydroxy group, a configuration of sugar chain hydroxy group, and tetracyclic rings substitution, affecting anthracyclines susceptibility for carbonyl reduction were identified.