Inhibition of polymorphic human carbonyl reductase 1 (CBR1) by the cardioprotectant flavonoid 7-monohydroxyethyl rutoside (monoHER).
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
The cardioprotectant monoHER inhibits CBR1 activity. CBR1 V88I genotype status and the type of anthracycline substrate dictate the inhibition of CBR1 activity.
Gonzalez-Covarrubias
Vanessa
V
Department of Pharmaceutical Sciences, The State University of New York at Buffalo, 545 Cooke Hall, Buffalo, New York 14260-1200, USA.
Kalabus
James L
JL
Blanco
Javier G
JG
D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors* / Q000235:genetics; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003627:Data Interpretation, Statistical; D003630:Daunorubicin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005838:Genotype; D006801:Humans; D006896:Hydroxyethylrutoside / Q000031:analogs & derivatives* / Q000494:pharmacology; D007700:Kinetics; D011994:Recombinant Proteins / Q000737:chemistry
C522803:7-monohydroxyethylrutoside; D000903:Antibiotics, Antineoplastic; D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D006896:Hydroxyethylrutoside; D011994:Recombinant Proteins; D004317:Doxorubicin; D000429:Alcohol Oxidoreductases; D003630:Daunorubicin