Inhibition of phenytoin bioactivation and teratogenicity by dietary n-3 fatty acids in mice.
Evidence suggests that the teratogenicity of the anticonvulsant drug phenytoin (DPH) can result from its bioactivation via embryonic 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 administered via intraperitoneal 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 evaluated in vivo covalent 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 teratogenicity via inhibition of embryonic prostaglandin synthase bioactivation of DPH.
Kubow
S
S
School of Dietetics and Human Nutrition, McGill University, Ste. Anne de Bellevue, Quebec, Canada.
D000014:Abnormalities, Drug-Induced / Q000517:prevention & control; D000818:Animals; D001711:Biotransformation / Q000187:drug effects; D000074263:Coconut Oil; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects; D004041:Dietary Fats / Q000494:pharmacology*; D004789:Enzyme Activation; D005227:Fatty Acids / Q000032:analysis; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology*; D005260:Female; D005395:Fish Oils / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000378:metabolism; D010672:Phenytoin / Q000378:metabolism / Q000633:toxicity*; D010743:Phospholipids / Q000737:chemistry; D010938:Plant Oils / Q000494:pharmacology; D011247:Pregnancy; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects; D012450:Safflower Oil / Q000494:pharmacology; D013723:Teratogens / Q000633:toxicity*; D014018:Tissue Distribution
D004041:Dietary Fats; D005227:Fatty Acids; D015525:Fatty Acids, Omega-3; D005395:Fish Oils; D010743:Phospholipids; D010938:Plant Oils; D013723:Teratogens; D010672:Phenytoin; D012450:Safflower Oil; D003577:Cytochrome P-450 Enzyme System; D011451:Prostaglandin-Endoperoxide Synthases; D000074263:Coconut Oil