TY - JOUR

T1 - The citrus-derived flavonoid naringenin exerts uterotrophic effects in female mice at human relevant doses

AU - Breinholt, Vibeke Miller

AU - Svendsen, Gitte Winkel

AU - Dragsted, Lars Ove

AU - Hossaini, Alireza

N1 - (Ekstern)

PY - 2004

Y1 - 2004

N2 - Gavage administration of the citrus flavonoid naringenin, 3′,4,5,7-tetrahydroxyflavanon for 4 consecutive days, to immature female mice (postnatal day 17-20) at 4 or 100 mg/kg b. wt. significantly increased uterine weights 3 and 4 times, respectively. Analysis of uterine oestrogen receptor α revealed that naringenin significantly increased the cytosolic concentration of oestrogen receptor α, whereas in nuclei the oestrogen receptor α concentration was significantly decreased as compared to the solvent control. This was in contrast to the positive control 17β-oestradiolacetate which acted as a true oestrogen by increasing the concentration of both total and nuclear oestrogen receptor α. Both naringenin and 17β-oestradiolacetate, however, significantly, induced nuclear oestrogen receptor α in the liver, suggesting a tissue specific effect of naringenin on oestrogen receptor α distribution. In order to investigate the tissue levels at which the uterotrophic effect was observed, the distribution of an oral dose of tritiated naringenin (4 mg/kg) was investigated in 3-week-old female mice. The radioactivity content (ng naringenin equivalents/g tissue) was found to be highest in the gastrointestinal-tract, followed by the kidneys and liver. Uterus and ovaries were also found to contain relatively high and approximately equal amounts of naringenin. The concentration of naringenin in uterus and ovaries was found to be ten times higher as compared to the mammary tissue. The urinary excretion of more than 25% of the administered dose, within 8 hr after dosing indicated that naringenin is absorbed extensively in mice. The plasma concentration of 0.5 μM found in the present study is similar to the peak plasma concentration of naringenin (0.6 μM) observed in man following ingestion of 400-760 ml of orange juice (Erlund et al. 2001). This could be taken to suggests that ingestion of orange juice and other citrus fruits and juices may give rise to sufficiently high tissue levels of naringenin in man to exert a biological effect.

AB - Gavage administration of the citrus flavonoid naringenin, 3′,4,5,7-tetrahydroxyflavanon for 4 consecutive days, to immature female mice (postnatal day 17-20) at 4 or 100 mg/kg b. wt. significantly increased uterine weights 3 and 4 times, respectively. Analysis of uterine oestrogen receptor α revealed that naringenin significantly increased the cytosolic concentration of oestrogen receptor α, whereas in nuclei the oestrogen receptor α concentration was significantly decreased as compared to the solvent control. This was in contrast to the positive control 17β-oestradiolacetate which acted as a true oestrogen by increasing the concentration of both total and nuclear oestrogen receptor α. Both naringenin and 17β-oestradiolacetate, however, significantly, induced nuclear oestrogen receptor α in the liver, suggesting a tissue specific effect of naringenin on oestrogen receptor α distribution. In order to investigate the tissue levels at which the uterotrophic effect was observed, the distribution of an oral dose of tritiated naringenin (4 mg/kg) was investigated in 3-week-old female mice. The radioactivity content (ng naringenin equivalents/g tissue) was found to be highest in the gastrointestinal-tract, followed by the kidneys and liver. Uterus and ovaries were also found to contain relatively high and approximately equal amounts of naringenin. The concentration of naringenin in uterus and ovaries was found to be ten times higher as compared to the mammary tissue. The urinary excretion of more than 25% of the administered dose, within 8 hr after dosing indicated that naringenin is absorbed extensively in mice. The plasma concentration of 0.5 μM found in the present study is similar to the peak plasma concentration of naringenin (0.6 μM) observed in man following ingestion of 400-760 ml of orange juice (Erlund et al. 2001). This could be taken to suggests that ingestion of orange juice and other citrus fruits and juices may give rise to sufficiently high tissue levels of naringenin in man to exert a biological effect.

UR - http://www.scopus.com/inward/record.url?scp=1642355257&partnerID=8YFLogxK

U2 - 10.1111/j.1742-7843.2004.pto_940106.x

DO - 10.1111/j.1742-7843.2004.pto_940106.x

M3 - Journal article

C2 - 14725612

AN - SCOPUS:1642355257

VL - 94

SP - 30

EP - 36

JO - Basic and Clinical Pharmacology and Toxicology

JF - Basic and Clinical Pharmacology and Toxicology

SN - 1742-7835

IS - 1

ER -