Evaluation of ovarian toxicity of sodium valproate (VPA) using cultured rat ovarian follicles.
Sodium valproate (VPA) is a major antiepileptic drug that is widely used for the treatment of epilepsy as well as other neuropsychiatric diseases. The present study was conducted to evaluate the ovarian toxicity of VPA using cultured rat ovarian follicles. Secondary follicles were isolated from the ovaries of 14-day-old female rats and cultured for 48 hr with VPA (0, 0.2, 1.0, and 5.0 mM). At 0, 24, and 48 hr of VPA treatment, follicular diameters were measured. After the culture, viability of follicles and expression of aromatase in the follicles were assessed, and progesterone, androstenedione, testosterone, and estradiol levels in culture media were measured. At all concentrations of VPA, follicular development was suppressed, and androstenedione, testosterone, estradiol, and combined levels of all steroid hormones tended to decrease in association with suppression of aromatase expression in granulosa cells. Additionally, the suppression of follicular development was associated with decreased viability of follicles and an increased progesterone level at 5.0 mM of VPA. The decrease in the combined levels of all steroid hormones implies that VPA suppresses the synthetic pathway from cholesterol to estradiol including de novo synthesis of cholesterol. In conclusion, VPA induces ovarian toxicity via suppression of development and abnormal steroid hormone synthesis in cultured rat ovarian follicles.
Safety Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd, Osaka, Japan. hiroshi-inada@ds-pharma.co.jp
Hiroshi
H
Inada
Kazuhiro
K
Chihara
Akihito
A
Yamashita
Izuru
I
Miyawaki
Chiharu
C
Fukuda
Yumi
Y
Tateishi
Takeshi
T
Kunimatsu
Juki
J
Kimura
Hitoshi
H
Funabashi
Takashi
T
Miyano
D000735:Androstenedione / Q000032:analysis / Q000096:biosynthesis; D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D001141:Aromatase / Q000378:metabolism; D004958:Estradiol / Q000032:analysis / Q000096:biosynthesis; D005260:Female; D006107:Granulosa Cells / Q000187:drug effects / Q000201:enzymology; D009924:Organ Culture Techniques; D006080:Ovarian Follicle / Q000166:cytology / Q000187:drug effects* / Q000473:pathology*; D011374:Progesterone / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013256:Steroids / Q000032:analysis / Q000096:biosynthesis; D013739:Testosterone / Q000032:analysis / Q000096:biosynthesis; D014635:Valproic Acid / Q000633:toxicity*
D000927:Anticonvulsants; D013256:Steroids; D013739:Testosterone; D000735:Androstenedione; D011374:Progesterone; D004958:Estradiol; D014635:Valproic Acid; D001141:Aromatase