Inhibitory Effect of Fruit Juices on the Doxorubicin Metabolizing Activity of Carbonyl Reductase 1.
Doxorubicin, an anthracycline anti-cancer drug, is effective for breast cancer and childhood lymphoma. Chronic cardiotoxicity has been known as a critical adverse effect of doxorubicin and is attributed to its metabolite doxorubicinol produced by carbonyl reductase 1 (CBR1, SDR21C1). Some flavonoids have been reported to act as inhibitors for CBR1, therefore, commercially available juices containing flavonoids are likely to be applicable as a prophylactic treatment against doxorubicin-induced cardiotoxicity by suppression of doxorubicinol production. In the study, fruit juices containing flavonoids were investigated for inhibitory effects on CBR1.



Recombinant CBR1 protein was subjected to in vitro enzymatic assays with/without juices. An apple juice and a grapefruit juice were selected in the present study as candidates capable of inhib-iting CBR1.



The enzymatic assays revealed that both juices potently inhibit the CBR1-mediated metabolic conversion of doxorubicin to doxorubicinol in concertation-dependent manner. The concentrations required for obtaining 50% inhibition (IC50) were 0.0012% (v/v) and 0.0014% (v/v) for apple and grapefruit juices, respectively. Additionally, it is worth noting that these juices showed inhibitory effects on doxorubicin metabolism by CBR1 even at very low concentrations (0.0001% (v/v)).



An apple juice and a grape fruit juice showed strong inhibitory effects on doxorubicin metabolism by CBR1 in vitro. These results suggest that the intake of flavonoid-containing juices can be a promising measure for protection against doxorubicin-induced cardiac toxicity, enabling patients to keep higher adherence with routine use in light of safety, economic performance and stable supply to market.
Laboratory of Biochemistry, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-kita, Tondabayashi, Osaka 584-8540, Japan.|Pharmaceutical Education Support Center, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University, 11-68 Koshien, 9-Bancho, Nishinomiya, Hyogo 663-8179, Japan.
Takeshi
T
Miura
Laboratory of Clinical Pharmacy and Therapeutics, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-kita, Tondabayashi, Osaka 584-8540, Japan.|Laboratory of Practical Pharmacy and Pharmaceutical Care, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-kita, Tondabayashi, Osaka 584-8540, Japan.
Katsutoshi
K
Nagai
Laboratory of Biochemistry, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-kita, Tondabayashi, Osaka 584-8540, Japan.
Shingo
S
Kaneshiro
Laboratory of Biochemistry, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-kita, Tondabayashi, Osaka 584-8540, Japan.|First Department of Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University, 11-68 Koshien, 9- Bancho, Nishinomiya 663-8179, Japan.
Ayako
A
Taketomi
First Department of Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University, 11-68 Koshien, 9- Bancho, Nishinomiya 663-8179, Japan.
Toshikatsu
T
Nakabayashi
Laboratory of Clinical Pharmacy and Therapeutics, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-kita, Tondabayashi, Osaka 584-8540, Japan.
Hiroki
H
Konishi
Laboratory of Biochemistry, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-kita, Tondabayashi, Osaka 584-8540, Japan.
Toru
T
Nishinaka
Laboratory of Biochemistry, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-kita, Tondabayashi, Osaka 584-8540, Japan.
Tomoyuki
T
Terada
D000429:Alcohol Oxidoreductases / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000737:chemistry*; D032083:Citrus paradisi / Q000737:chemistry*; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000737:chemistry*; D005419:Flavonoids / Q000737:chemistry; D000067030:Fruit and Vegetable Juices; D006801:Humans; D027845:Malus / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry
D000970:Antineoplastic Agents; D005419:Flavonoids; D011994:Recombinant Proteins; D004317:Doxorubicin; D000429:Alcohol Oxidoreductases; C531129:CBR1 protein, human; C010013:adriamycinol
CBR1; SDR21C1; doxirubicinol; flavonoid; juice.; polyphenol