期刊
DRUG METABOLISM AND DISPOSITION
卷 36, 期 10, 页码 2113-2120出版社
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/dmd.108.022251
关键词
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资金
- German Federal Ministry for Education and Science (BMBF) [01GS0421, 0313080I]
- Deutsche Forschungsgemeinschaft (DFG) [MA 1704/5-1]
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 K-m of similar to 140 mu M. Of six enzymes found to reduce DOX, K-m 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.
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