Sex differences in improved efficacy of doxorubicin chemotherapy in Cbr1+/− mice

Freeland, Megan M.; Angulo, Jackeline; Davis, Alison L.; Flook, Adam M.; Garcia, Brittany L.; King, Nathan A.; Mangibin, Samuelle K.; Paul, Kristin; Prosser, Megan E.; Sata, Nicole; Bentley, J; Olson, Lisa E.

doi:10.1097/cad.0b013e3283512726

Cited by 8 publications

(5 citation statements)

References 43 publications

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“…Sex hormones may also participate in CBR1 transcriptional regulation, as a marked difference in Cbr1 expression between male and female mice has been reported (Freeland et al, 2012). This finding points to the possibility that the anticancer as well as adverse effects of anthracyclines may differ between genders.…”

Section: The Transcriptional Regulation Of Cbr1mentioning

confidence: 86%

The modulation of carbonyl reductase 1 by polyphenols

Boušová

Skálová

Souček

et al. 2015

Drug Metabolism Reviews

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Carbonyl reductase 1 (CBR1), an enzyme belonging to the short-chain dehydrogenases/reductases family, has been detected in all human tissues. CBR1 catalyzes the reduction of many xenobiotics, including important drugs (e.g. anthracyclines, nabumetone, bupropion, dolasetron) and harmful carbonyls and quinones. Moreover, it participates in the metabolism of a number of endogenous compounds and it may play a role in certain pathologies. Plant polyphenols are not only present in many human food sources, but are also a component of many popular dietary supplements and herbal medicines. Many studies reviewed herein have demonstrated the potency of certain flavonoids, stilbenes and curcuminoids in the inhibition of the activity of CBR1. Interactions of these polyphenols with transcriptional factors, which regulate CBR1 expression, have also been reported in several studies. As CBR1 plays an important role in drug metabolism as well as in the protection of the organism against potentially harmful carbonyls, the modulation of its expression/activity may have significant pharmacological and/or toxicological consequences. Some polyphenols (e.g. luteolin, apigenin and curcumin) have been shown to be very potent CBR1 inhibitors. The inhibition of CBR1 seems useful regarding the increased efficacy of anthracycline therapy, but it may cause the worse detoxification of reactive carbonyls. Nevertheless, all known information about the interactions of polyphenols with CBR1 have only been based on the results of in vitro studies. With respect to the high importance of CBR1 and the frequent consumption of polyphenols, in vivo studies would be very helpful for the evaluation of risks/benefits of polyphenol interactions with CBR1.

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Section: The Transcriptional Regulation Of Cbr1mentioning

confidence: 86%

The modulation of carbonyl reductase 1 by polyphenols

Boušová

Skálová

Souček

et al. 2015

Drug Metabolism Reviews

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“…Several investigators attributed this sexual dimorphism to the cardioprotection conferred by estrogen in female experimental animals [11, 13, 45]. Intriguingly, another study showed that the expression of carbonyl reductase, a major DOX-metabolizing enzyme, is higher in the kidney and liver of female than in male mice [46]. The authors suggested that higher expression of carbonyl reductase may make female mice more sensitive to DOX-induced toxicity; however, DOX-induced cardiotoxicity was not actually assessed in their study [46].…”

Section: Discussionmentioning

confidence: 99%

“…Intriguingly, another study showed that the expression of carbonyl reductase, a major DOX-metabolizing enzyme, is higher in the kidney and liver of female than in male mice [46]. The authors suggested that higher expression of carbonyl reductase may make female mice more sensitive to DOX-induced toxicity; however, DOX-induced cardiotoxicity was not actually assessed in their study [46]. Therefore, the underlying mechanisms of sexual dimorphism in DOX-induced toxicity are still poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Sex-dependent alteration of cardiac cytochrome P450 gene expression by doxorubicin in C57Bl/6 mice

et al. 2017

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BackgroundThere is inconclusive evidence about the role of sex as a risk factor for doxorubicin (DOX)-induced cardiotoxicity. Recent experimental studies have shown that adult female rats are protected against DOX-induced cardiotoxicity. However, the mechanisms of this sexual dimorphism are not fully elucidated. We have previously demonstrated that DOX alters the expression of several cytochrome P450 (CYP) enzymes in the hearts of male rats. Nevertheless, the sex-dependent effect of DOX on the expression of CYP enzymes is still not known. Therefore, in the present study, we determined the effect of acute DOX exposure on the expression of CYP genes in the hearts of both male and female C57Bl/6 mice.MethodsAcute DOX cardiotoxicity was induced by a single intraperitoneal injection of 20 mg/kg DOX in male and female adult C57Bl/6 mice. Cardiac function was assessed 5 days after DOX exposure by trans-thoracic echocardiography. Mice were euthanized 1 day or 6 days after DOX or saline injection. Thereafter, the hearts were harvested and weighed. Heart sections were evaluated for pathological lesions. Total RNA was extracted and expression of natriuretic peptides, inflammatory and apoptotic markers, and CYP genes was measured by real-time PCR.ResultsAdult female C57Bl/6 mice were protected from acute DOX-induced cardiotoxicity as they show milder pathological lesions, less inflammation, and faster recovery from DOX-induced apoptosis and DOX-mediated inhibition of beta-type natriuretic peptide. Acute DOX exposure altered the gene expression of multiple CYP genes in a sex-dependent manner. In 24 h, DOX exposure caused male-specific induction of Cyp1b1 and female-specific induction of Cyp2c29 and Cyp2e1.ConclusionsAcute DOX exposure causes sex-dependent alteration of cardiac CYP gene expression. Since cardiac CYP enzymes metabolize several endogenous compounds to biologically active metabolites, sex-dependent alteration of CYP genes may play a role in the sexual dimorphism of acute DOX-induced cardiotoxicity.Electronic supplementary materialThe online version of this article (doi:10.1186/s13293-016-0124-4) contains supplementary material, which is available to authorized users.

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“…Moreover, the highest DOX concentration was found in the urine of DOX-IN-treated animals after the last injection, which implies the higher organ toxicity of the conventional DOX formulation compared to the nanoformulation. As DOX is mostly metabolized by the liver, the higher excretion of unchanged DOX means a lower capacity of the liver to metabolize it [37,38]. This was also evident in the results obtained for DOXol and DOXon concentrations, which decreased with the number of applications in animals treated with DOX-IN.…”

Section: Discussionmentioning

confidence: 65%

High-Throughput Method for the Simultaneous Determination of Doxorubicin Metabolites in Rat Urine after Treatment with Different Drug Nanoformulations

Zorić

Drinković²,

Micek

et al. 2022

Molecules

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Doxorubicin (DOX) is one of the most effective cytotoxic agents against malignant diseases. However, the clinical application of DOX is limited, due to dose-related toxicity. The development of DOX nanoformulations that significantly reduce its toxicity and affect the metabolic pathway of the drug requires improved methods for the quantitative determination of DOX metabolites with high specificity and sensitivity. This study aimed to develop a high-throughput method based on high-performance liquid chromatography with fluorescence detection (HPLC-FD) for the quantification of DOX and its metabolites in the urine of laboratory animals after treatment with different DOX nanoformulations. The developed method was validated by examining its specificity and selectivity, linearity, accuracy, precision, limit of detection, and limit of quantification. The DOX and its metabolites, doxorubicinol (DOXol) and doxorubicinone (DOXon), were successfully separated and quantified using idarubicin (IDA) as an internal standard (IS). The linearity was obtained over a concentration range of 0.05–1.6 μg/mL. The lowest limit of detection and limit of quantitation were obtained for DOXon at 5.0 ng/mL and 15.0 ng/mL, respectively. For each level of quality control (QC) samples, the inter- and intra-assay precision was less than 5%. The accuracy was in the range of 95.08–104.69%, indicating acceptable accuracy and precision of the developed method. The method was applied to the quantitative determination of DOX and its metabolites in the urine of rats treated by novel nanoformulated poly(lactic-co-glycolic acid) (DOX-PLGA), and compared with a commercially available DOX solution for injection (DOX-IN) and liposomal-DOX (DOX-MY).

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Sex differences in improved efficacy of doxorubicin chemotherapy in Cbr1+/− mice

Cited by 8 publications

References 43 publications

The modulation of carbonyl reductase 1 by polyphenols

The modulation of carbonyl reductase 1 by polyphenols

Sex-dependent alteration of cardiac cytochrome P450 gene expression by doxorubicin in C57Bl/6 mice

High-Throughput Method for the Simultaneous Determination of Doxorubicin Metabolites in Rat Urine after Treatment with Different Drug Nanoformulations

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