Carbonyl reductase [NADPH] 1
carbonyl reductase (NADPH) activity
Inhibition of polymorphic human carbonyl reductase 1 (CBR1) by the cardioprotectant flavonoid 7-monohydroxyethyl rutoside (monoHER).
<h4>Purpose</h4>Carbonyl reductase 1 (CBR1) reduces the anticancer anthracyclines doxorubicin and daunorubicin into the cardiotoxic metabolites doxorubicinol and daunorubicinol. We evaluated whether the cardioprotectant monoHER inhibits the activity of polymorphic CBR1.<h4>Methods</h4>We performed enzyme kinetic studies with monoHER, CBR1 (CBR1 V88 and CBR1 I88) and anthracycline substrates. We also characterized CBR1 inhibition by the related flavonoids triHER and quercetin.<h4>Results</h4>MonoHER inhibited the activity of CBR1 V88 and CBR1 I88 in a concentration-dependent manner. The IC(50) values of monoHER were lower for CBR1 I88 compared to CBR1 V88 for the substrates daunorubicin and doxorubicin (daunorubicin, IC(50)-CBR1 I88 = 164 microM vs. IC(50)-CBR1 V88 = 219 microM; doxorubicin, IC(50)-CBR1 I88 = 37 microM vs. IC(50)-CBR1 V88 = 59 microM; p < 0.001). Similarly, the flavonoids triHER and quercetin exhibited lower IC(50) values for CBR1 I88 compared to CBR1 V88 (p < 0.001). MonoHER acted as a competitive CBR1 inhibitor when using daunorubicin as a substrate Ki = 45 +/- 18 microM. MonoHER acted as an uncompetitive CBR1 inhibitor for the small quinone substrate menadione Ki = 33 +/- 17 microM.<h4>Conclusions</h4>The cardioprotectant monoHER inhibits CBR1 activity. CBR1 V88I genotype status and the type of anthracycline substrate dictate the inhibition of CBR1 activity.