Reduction of 13-deoxydoxorubicin and daunorubicinol anthraquinones by human carbonyl reductase.
Carbonyl reductase (CR) catalyzes the nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reduction of several carbonyls. Anthracyclines used to treat cancer are reduced by CR at the C13 carbonyl and the resulting metabolites are implicated in the cardiotoxicity associated with anthracycline therapy. CR also is believed to have a role in detoxifying quinones, raising the question whether CR catalyzes reduction of anthracycline quinones. Steady-state kinetic studies were done with several anthraquinone-containing compounds, including 13-deoxydoxorubicin and daunorubicinol, which lack the C13 carbonyl, thus unmasking the anthraquinone for study. k(cat) and k(cat)/K(m) values for 13-deoxydoxorubicin and daunorubicinol were nearly identical, indicating that that the efficiency of quinone reduction was unaffected by the differences at the C13 position. k(cat) and k(cat)/K(m) values were much smaller for the analogs than for the parent compounds, suggesting that the C13 carbonyl is preferred as a substrate over the quinone. CR also reduced structurally related quinone molecules with less favorable catalytic efficiency. Modeling studies with doxorubicin and carbonyl reductase revealed that methionine 234 sterically hinder the rings adjacent to the quinone, thus accounting for the lower catalytic efficiency. Reduction of the anthraquinones may further define the role of CR in anthracycline metabolism and may influence anthracycline cytotoxic and cardiotoxic mechanisms.
Slupe
Andrew
A
Department of Chemistry, Boise State University, Boise, ID 83725, USA.
Williams
Berea
B
Larson
Corianton
C
Lee
Laura M
LM
Primbs
Toby
T
Bruesch
Amanda J
AJ
Bjorklund
Chad
C
Warner
Don L
DL
Peloquin
Jeffrey
J
Shadle
Susan E
SE
Gambliel
Hervé A
HA
Cusack
Barry J
BJ
Olson
Richard D
RD
Charlier
Henry A
HA
D000429:Alcohol Oxidoreductases / Q000302:isolation & purification / Q000378:metabolism*; D000818:Animals; D000880:Anthraquinones / Q000737:chemistry; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D010084:Oxidation-Reduction; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins
D000880:Anthraquinones; D011994:Recombinant Proteins; D004317:Doxorubicin; D000429:Alcohol Oxidoreductases; C010013:adriamycinol; C000847:daunorubicinol; D003630:Daunorubicin