The systemic and gonadal toxicity of 3-methylcholanthrene is prevented by daily administration of α-naphthoflavone

Rhon‐Calderón, Eric A.; Galarza, Rocío Alejandra; Lomniczi, Alejandro; Faletti, A.

doi:10.1016/j.tox.2016.05.005

Cited by 7 publications

(22 citation statements)

References 60 publications

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“…[79][80][81][82] Additionally,arecent study revealed that a-NF has aclearstimulatory effect on the ovaries, and prevents both systemic and gonadal 3-methylcholanthrene-induced toxicity. [83] In particular, a-NF has attracted considerable interest in modulating cyto-chromeP 450s. In as tudy performed by Shimada et al, a-NF was found to exhibit strong suppressive effects on recombinant human CYP1B1 and1 A2, with IC 50 values of 5a nd 6nm, respectively,b ut to am uch lesser extento nC YP1A1 (IC 50 : 60 nm).…”

Section: Interactions Of Naphthoflavonoids With Cyp1smentioning

confidence: 99%

“…The biological functions of α‐NF have been shown to be involved in inhibiting aromatase, drug transporters and platelet aggregation, as well as inducing apoptosis, thus contributing to the treatment of cancer and arterial thromboembolism . Additionally, a recent study revealed that α‐NF has a clear stimulatory effect on the ovaries, and prevents both systemic and gonadal 3‐methylcholanthrene‐induced toxicity . In particular, α‐NF has attracted considerable interest in modulating cytochrome P450s.…”

Section: Interactions Of Naphthoflavonoids With Cyp1smentioning

confidence: 99%

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Flavonoids and Naphthoflavonoids: Wider Roles in the Modulation of Cytochrome P450 Family 1 Enzymes

et al. 2016

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The human cytochrome P450 family 1 enzymes consist of three members, CYP1A1, CYP1A2 and CYP1B1, which are predominantly involved in the phase I metabolism of xenobiotics. Because they have been implicated in carcinogenesis, cancer progression, and drug resistance, the inhibition of these enzymes has been widely considered an effective oncological therapeutic strategy. Some natural and synthetic flavonoids and naphthoflavonoids have been extensively documented to exert pronounced influence in the modulation of CYP1s, including functioning as inhibitors, substrates, and aryl hydrocarbon receptor (AhR) ligands. However, the molecular determinants behind these effects are still unknown. This review summarizes the structural features responsible for the CYP1 inhibitory effects of the reported flavonoids and naphthoflavonoids. Additionally, a three-dimensional quantitative structure-activity relationship (3D-QSAR) study was performed to better understand the effect of their structural properties on biological activities. We hope this review provides a useful foundation for the rational design of potent and selective CYP1 isozyme inhibitors, thereby accelerating the drug discovery process.

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Section: Interactions Of Naphthoflavonoids With Cyp1smentioning

confidence: 99%

Section: Interactions Of Naphthoflavonoids With Cyp1smentioning

confidence: 99%

Flavonoids and Naphthoflavonoids: Wider Roles in the Modulation of Cytochrome P450 Family 1 Enzymes

et al. 2016

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“…All animals (six to eight per group) were killed by decapitation in the afternoon of the second estrous cycle. Doses were selected based on previous studies showing that they are effective to destroy primordial follicles and inhibit both follicular growth and ovulation (Borman et al 2000; Rhon Calderón et al 2016).…”

Section: Methodsmentioning

confidence: 99%

“…Some reproductive processes such as fertility, gametogenesis, follicular development (Benedict et al 2000, 2003; Barnett et al 2007a, 2007b), and ovarian function (Hernández-Ochoa et al 2009, 2010) are dependent on the activation of AhR. Previously, we found that daily exposure to low doses of 3MC during the pubertal period in rats disrupt both follicular growth and ovulation through an AhR-dependent mechanism (Rhon-Calderón et al 2016). Therefore, and to provide new insights into the toxicity mechanism of 3MC in the ovary, in the present study, we investigated the effect of daily low doses of 3MC on the expression of selected groups of ovary-expressed genes enriched in putative AhR binding sites, in rats.…”

Section: Introductionmentioning

confidence: 99%

Changes in the expression of genes involved in the ovarian function of rats caused by daily exposure to 3-methylcholanthrene and their prevention by α-naphthoflavone

et al. 2017

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Daily exposure to low doses of 3-methylcholanthrene (3MC) during the pubertal period in rats disrupts both follicular growth and ovulation. Thus, to provide new insights into the toxicity mechanism of 3MC in the ovary, here we investigated the effect of daily exposure to 3MC on selected ovarian genes, the role of the aryl hydrocarbon receptor (AhR) and the level of epigenetic remodeling of histone post-transcriptional modifications. Immature rats were daily injected with 3MC (0.1 or 1 mg/kg) and mRNA expression of genes involved in different ovarian processes were evaluated. Of the 29 genes studied, 18 were up-regulated, five were down-regulated and six were not altered. To assess whether AhR was involved in these changes, we used the chromatin immunoprecipitation assay. 3MC increased AhR binding to promoter regions of genes involved in Notch signaling (Hes1, Jag1), activation of primordial follicles (Cdk2), cell adhesion (Icam1), stress and tumor progression (Dnajb6), apoptosis (Bax, Caspase-9) and expression of growth and transcription factors (Igf2, Sp1). Studying the trimethylation and acetylation of histone 3 (H3K4me3 and H3K9Ac, respectively) of these genes, we found that 3MC increased H3K4me3 in Cyp1a1, Jag1, Dnajb6, Igf2, Notch2, Adamts1, Bax and Caspase-9, and H3K9Ac in Cyp1a1, Jag1, Cdk2, Dnajb6, Igf2, Icam1, and Sp1. Co-treatment with α-naphthoflavone (αNF), a specific antagonist of AhR, prevented almost every 3MC-induced changes. Despite the low dose used in these experiments, daily exposure to 3MC induced changes in both gene expression and epigenomic remodeling, which may lead to premature ovarian failure.

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“…26,27 To this end, both femurs were extracted to obtain a suspension of bone marrow cells by flushing with phosphatebuffered saline, using a 1-mL syringe with a 21-guage needle. The alkaline comet assay was also used to quantify the damage in the DNA in oocytes as a measure of possible damage in germ cells.…”

Section: Cytotoxicity Assaysmentioning

confidence: 99%

Maternal Overweight Disrupts the Sexual Maturation of the Offspring

et al. 2017

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The aims of the present work were to study the effect of maternal overweight and obesity on the ovarian reserve, follicular development, and ovulation of the offspring and to assess whether this maternal condition alters oocyte integrity. To this end, female offspring from rats fed standard (OSD) or cafeteria (OCD) diet were used. Body weight, vaginal opening, and estrous cycle were recorded and ovaries were obtained on the day of the second estrus. In addition, ovarian weight, ovulation rate (measured by the number of oocytes within oviducts), follicular development (determined by histology), and oocyte integrity were examined. The OCD were divided into 2 groups: offspring from rats with 17% and 28% of overweight (OCD17 and OCD28, respectively). Both OCD groups showed higher body weight, but OCD28 also exhibited early vaginal opening and higher ovarian weight and glycemia at euthanasia compared with OSD. Both OCD17 and OCD28 had lower number of primordial and primary follicles, and only OCD28 exhibited lower number of antral follicles, all compared with OSD rats. In addition, both OCD17 and OCD28 had higher ovulation rate than controls, and OCD28 had lower number of healthy oocytes, which, in turn, exhibited morphological alterations such as larger perivitelline space and zona pellucida than those of control animals. These results suggest that maternal overweight may severely affect the reproductive ability of the offspring, likely as a result of altering the organogenesis.

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The systemic and gonadal toxicity of 3-methylcholanthrene is prevented by daily administration of α-naphthoflavone

Cited by 7 publications

References 60 publications

Flavonoids and Naphthoflavonoids: Wider Roles in the Modulation of Cytochrome P450 Family 1 Enzymes

Flavonoids and Naphthoflavonoids: Wider Roles in the Modulation of Cytochrome P450 Family 1 Enzymes

Changes in the expression of genes involved in the ovarian function of rats caused by daily exposure to 3-methylcholanthrene and their prevention by α-naphthoflavone

Maternal Overweight Disrupts the Sexual Maturation of the Offspring

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