Inhibition of phenytoin bioactivation and teratogenicity by dietary n-3 fatty acids in mice

• Published in: Lipids Vol. 27; no. 9; pp. 721 - 728
• Main Author: Kubow, S. (McGill University, Ste. Anne de Bellevue, Quebec, Canada)
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer‐Verlag 01.09.1992; Springer
• Subjects: Abnormalities, Drug-Induced - prevention & control; ACIDE GRAS INSATURE; ACIDOS GRASOS INSATURADOS; ACTIVIDAD ENZIMATICA; ACTIVITE ENZYMATIQUE; Animals; BINDING; Biological and medical sciences; Biotransformation - drug effects; Coconut Oil; CORPS GRAS; COVALENT BINDING; CYTOCHROME P-450; Cytochrome P-450 Enzyme System - drug effects; DIET; DIETA; Dietary Fats - pharmacology; Embryology: invertebrates and vertebrates. Teratology; EMBRYOS; Enzyme Activation; ENZYMIC ACTIVITY; FATS; Fatty Acids - analysis; Fatty Acids, Omega-3 - pharmacology; Female; Fish Oils - pharmacology; FOIE; Fundamental and applied biological sciences. Psychology; GENETIC DISORDERS; GRASAS; HIGADO; INHIBICION; INHIBITION; LIVER; Liver - drug effects; Liver - enzymology; MADRE; MEDICAMENT NEUROTROPE; MEDICAMENTOS NEUROTROPICOS; MERE; METALLOPROTEINE; METALLOPROTEINS; METALPROTEINAS; MICE; Mice, Inbred Strains; Microsomes, Liver - metabolism; MOTHERS; NEUROTROPIC DRUGS; NUTRIENT DRUG INTERACTIONS; OXIDOREDUCTASES; OXIDORREDUCTASAS; OXYDOREDUCTASE; Phenytoin - metabolism; Phenytoin - toxicity; Phospholipids - chemistry; Plant Oils - pharmacology; POLYENOIC FATTY ACIDS; Pregnancy; PROSTAGLANDIN SYNTHASE; Prostaglandin-Endoperoxide Synthases - drug effects; RATON; REGIME ALIMENTAIRE; Safflower Oil - pharmacology; SOURIS; TERATOGENESIS; Teratogens - toxicity; TERATOLOGY; Teratology. Teratogens; Tissue Distribution; TRASTORNOS GENETICOS; TROUBLE GENETIQUE; UNSATURATED FATTY ACIDS; Dietary allowance; Vertebrata; Mammalia; Mouse; Teratogénesis; Rodentia; Activation; Anticonvulsant; Inhibition; Fatty acids; Hydantoins; Nutritional status
• ISSN: 0024-4201; 1558-9307
• DOI: 10.1007/BF02536032

Evidence suggests that the teratogenicity of the anticonvulsant drug phenytoin (DPH) can result from its bioactivationvia 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 administeredvia 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 evaluatedin 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 teratogenicityvia inhibition of embryonic prostaglandin synthase bioactivation of DPH.