title: Reduction of 13-deoxydoxorubicin and daunorubicinol anthraquinones by human carbonyl reductase.
abstract: 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.
authors.affiliation: Department of Chemistry, Boise State University, Boise, ID 83725, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Slupe
authors.forename: Berea
authors.initials: B
authors.lastname: Williams
authors.forename: Corianton
authors.initials: C
authors.lastname: Larson
authors.forename: Laura M
authors.initials: LM
authors.lastname: Lee
authors.forename: Toby
authors.initials: T
authors.lastname: Primbs
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Bruesch
authors.forename: Chad
authors.initials: C
authors.lastname: Bjorklund
authors.forename: Don L
authors.initials: DL
authors.lastname: Warner
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Peloquin
authors.forename: Susan E
authors.initials: SE
authors.lastname: Shadle
authors.forename: Hervé A
authors.initials: HA
authors.lastname: Gambliel
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Cusack
authors.forename: Richard D
authors.initials: RD
authors.lastname: Olson
authors.forename: Henry A
authors.initials: HA
authors.lastname: Charlier
mesh_terms: 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
chemical_list: D000880:Anthraquinones; D011994:Recombinant Proteins; D004317:Doxorubicin; D000429:Alcohol Oxidoreductases; C010013:adriamycinol; C000847:daunorubicinol; D003630:Daunorubicin