Carbonyl reductase 1 expression influences daunorubicin metabolism in acute myeloid leukemia.

European Journal of Clinical Pharmacology
Savitha VaratharajanPoonkuzhali Balasubramanian

Abstract

The present study aimed to investigate the role of expression of daunorubicin-metabolizing enzymes carbonyl reductase 1 and 3 (CBR1 and CBR3) on the in vitro cytotoxicity of daunorubicin in primary acute myeloid leukemia (AML) cells and the effect of genetic variants in CBR1 and CBR3 on the plasma pharmacokinetics of daunorubicin and daunorubicinol (DOL) in AML patients. RNA expression of CBR1 and CBR3, intracellular daunorubicin and DOL levels, and in vitro cytotoxicity of daunorubicin were measured in bone marrow mononuclear cells of 104 adult AML patients. Plasma pharmacokinetics of daunorubicin and DOL was measured in 24 patients receiving daunorubicin-based induction chemotherapy for AML. Increased expression of CBR1 significantly reduced the in vitro cytotoxicity of daunorubicin and also positively correlated with intracellular DOL levels. Polymorphisms in CBR1 and CBR3 did not show any association with intracellular daunorubicin or DOL levels, but there was a trend towards significant increase in plasma daunorubicin systemic exposure in patients with a variant genotype for CBR1 polymorphism rs25678. This pilot study suggests that CBR1 RNA expression may be helpful in identifying AML patients at risk of developing resista...Continue Reading

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Citations

Sep 30, 2015·Drug Metabolism Reviews·Iva BoušováPetra Matoušková
Sep 3, 2014·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Joel A KrauserPiet Swart
Oct 28, 2016·Cancer Chemotherapy and Pharmacology·Savitha VaratharajanPoonkuzhali Balasubramanian
Jul 18, 2017·Expert Opinion on Drug Metabolism & Toxicology·Sophia M Shi, Li Di

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