Inhibition of phenytoin bioactivation and teratogenicity by dietary n−3 fatty acids in mice
Inhibition of phenytoin bioactivation and teratogenicity by dietary n−3 fatty acids in mice
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作者：
S. Kubow
有证据表明，抗惊厥药物苯妥英(DPH)的致畸作用可能源于其通过胚胎前列腺素合成酶和/或母体细胞色素P450的生物激活。本研究探讨了饲料中n-−-3脂肪酸能否降低苯丙氨酸的生物活性和致畸性。雌性CD-1小鼠在受孕前和整个妊娠期间分别饲喂含有2wt%红花油和10wt%氢化椰子油、红花油或鱼肝油/亚麻籽油混合物(CLO/LO)的饲料三周。DPH(55或65 mg/kg)分别于妊娠第12天和第13天0900天经腹腔注射给妊娠小鼠，并于第19天对胎儿进行畸形学评估。一项类似的饮食研究评估了放射性标记DPH在第12天的活体共价结合，并在24小时后处死大鼠。在CLO/LO组中，观察到DPH诱导的腭裂减少，DPH与胚胎蛋白的共价结合减少。饲喂ClO/LO可促进n-−-3脂肪酸进入胚胎，抑制胚胎前列腺素合成酶活性。不同饲粮处理组母猪肝脏细胞色素P450活性差异不显著。这些结果表明，饲料中添加n-−-3脂肪酸可通过抑制胚胎前列腺素合成酶的活性来降低其致畸率。
Evidence suggests that the teratogenicity of the anticonvulsant drug phenytoin (DPH) can result from its bioactivationviaembryonic prostaglandin synthase and/or maternal cytochromes P450. This study examined whether DPH bioactivation and teratogenicity could be reduced by dietary n−3 fatty acids. Female CD‐1 mice were fed diets containing 2 wt% safflower oil and 10 wt% of either hydrogenated coconut oil, safflower oil, or a cod liver oil/linseed oil mixture (CLO/LO) for three weeks prior to impregnation and throughout gestation. DPH (55 or 65 mg/kg) was administeredviaintraperitoneal injections to pregnant mice at 0900 on gestational days 12 and 13, and on day 19 fetuses were given teratologic assessments. A similar dietary study evaluatedin vivocovalent binding of radiolabeled DPH administered on day 12, and dams were killed 24 h later. A reduction in DPH‐induced cleft palates and a decrease in DPH covalent binding to embryonic protein was observed in the CLO/LO group. Feeding CLO/LO enhanced incorporation of n−3 fatty acids into embryos and inhibited embryonic prostaglandin synthase activity. No differences in maternal hepatic cytochromes P450 activities were observed among dietary treatments. These data indicate that dietary n−3 fatty acids could reduce DPH teratogenicityviainhibition of embryonic prostaglandin synthase bioactivation of DPH.