In terms of
drug disposal and metabolism SDR21C1 (
carbonyl reductase 1; CBR1) exerts an assorted substrate spectrum among a large variety of clinically relevant substances. Additionally, this
short-chain dehydrogenase/reductase is extensively expressed in most tissues of the human body, thus underpinning its role in
xenobiotic metabolism. Reduction of the chemotherapeutic
daunorubicin (DAUN) to
daunorubicinol (DAUNol) is a prominent example of its metabolic properties in terms of chemoresistance and
cardiotoxicity. The hop-derived prenylated
chalcone xanthohumol (XN) and its physiological metabolites
isoxanthohumol (IX) and
8-prenylnaringenin (8-PN) have previously been reported to inhibit other DAUN reducing
reductases and
dehydrogenases including AKR1B1 and AKR1B10. Also with regard to their effects by means of interacting with
cancer-related molecular pathways, XN and related prenylated
flavonoids in particular have been in the focus of recent studies. In this study, inhibitory properties of these substances were examined with CBR1-mediated
2,3-hexanedione and DAUN reduction. All substances tested in this study turned out to efficiently inhibit recombinant human CBR1 within a low micromolar to submicromolar range. Among the substances tested, 8-PN turned out to be the most effective inhibitor when using
2,3-hexanedione as a substrate (Ki(app) = 180 ± 20 nM). Inhibition rates of recombinant CBR1-mediated DAUN reduction were somewhat weaker with IC50-values ranging from 11 to 20 μM. XN, IX and 8-PN also efficiently inhibited DAUN reduction by SW480
colon adenocarcinoma cytosol (IC50 = 3.71 ± 0.26 μM with 8-PN as inhibitor). This study identifies prenylated inhibitors, which might potentially interact with endogenous CBR1-driven (de-)toxication systems.