Title:Inhibitory Effect of Fruit Juices on the Doxorubicin Metabolizing Activity of Carbonyl Reductase 1
Volume: 11
Issue: 1
Author(s): Takeshi Miura*, Katsutoshi Nagai, Shingo Kaneshiro, Ayako Taketomi, Toshikatsu Nakabayashi, Hiroki Konishi, Toru Nishinaka and Tomoyuki Terada
Affiliation:
- Pharmaceutical Education Support Center, School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University, 11-68 Koshien, 9-Bancho, Nishinomiya, Hyogo 663-8179,Japan
Keywords:
CBR1, SDR21C1, flavonoid, polyphenol, doxirubicinol, juice.
Abstract: Background and Objective: 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.
Method: 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.
Results: 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)).
Conclusion: 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.
