Carbonyl reductase 1 is a predominant doxorubicin reductase in the human liver.
A first step in the enzymatic disposition of the antineoplastic drug doxorubicin (DOX) is the reduction to doxorubicinol (DOX-OL). Because DOX-OL is less antineoplastic but more cardiotoxic than the parent compound, the individual rate of this reaction may affect the antitumor effect and the risk of DOX-induced heart failure. Using purified enzymes and human tissues we determined enzymes generating DOX-OL and interindividual differences in their activities. Human tissues express at least two DOX-reducing enzymes. High-clearance organs (kidney, liver, and the gastrointestinal tract) express an enzyme with an apparent Km of approximately 140 microM. Of six enzymes found to reduce DOX, Km values in this range are exhibited by carbonyl reductase 1 (CBR1) and aldo-keto reductase (AKR) 1C3. CBR1 is expressed in these three organs at higher levels than AKR1C3, whereas AKR1C3 has higher catalytic efficiency. However, inhibition constants for DOX reduction with 4-amino-1-tert-butyl-3-(2-hydroxyphenyl)pyrazolo[3,4-d]pyrimidine (an inhibitor that can discriminate between CBR1 and AKR1C3) were identical for CBR1 and human liver cytosol, but not for AKR1C3. These results suggest that CBR1 is a predominant hepatic DOX reductase. In cytosols from 80 human livers, the expression level of CBR1 and the activity of DOX reduction varied >70- and 22-fold, respectively, but showed no association with CBR1 gene variants found in these samples. Instead, the interindividual differences in CBR1 expression and activity may be mediated by environmental factors acting via recently identified xenobiotic response elements in the CBR1 promoter. The variability in the CBR1 expression may affect outcomes of therapies with DOX, as well as with other CBR1 substrates.
Kassner
Nina
N
Department of Pharmacology, Johannes Gutenberg University Mainz, Obere Zahlbacher Str. 67, D-55101 Mainz, Germany.
Huse
Klaus
K
Martin
Hans-Jörg
HJ
Gödtel-Armbrust
Ute
U
Metzger
Annegret
A
Meineke
Ingolf
I
Brockmöller
Jürgen
J
Klein
Kathrin
K
Zanger
Ulrich M
UM
Maser
Edmund
E
Wojnowski
Leszek
L
D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001706:Biopsy; D015153:Blotting, Western; D002851:Chromatography, High Pressure Liquid; D004317:Doxorubicin / Q000493:pharmacokinetics*; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics
D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D004317:Doxorubicin; D000429:Alcohol Oxidoreductases; C531129:CBR1 protein, human