Modulation of phenytoin teratogenicity and embryonic covalent binding by acetylsalicylic acid, caffeic acid, and alpha-phenyl-N-t-butylnitrone: implications for bioactivation by prostaglandin synthetase

Journal Article · Wed Feb 01 04:00:00 EST 1989 · Toxicol. Appl. Pharmacol.; (United States)

DOI:https://doi.org/10.1016/0041-008X(89)90325-6· OSTI ID:6174102

Wells, P G; Zubovits, J T; Wong, S T; Molinari, L M; Ali, S

Teratogenicity of the anticonvulsant drug phenytoin is thought to involve its bioactivation by cytochromes P-450 to a reactive arene oxide intermediate. We hypothesized that phenytoin also may be bioactivated to a teratogenic free radical intermediate by another enzymatic system, prostaglandin synthetase. To evaluate the teratogenic contribution of this latter pathway, an irreversible inhibitor of prostaglandin synthetase, acetylsalicylic acid (ASA), 10 mg/kg intraperitoneally (ip), was administered to pregnant CD-1 mice at 9:00 AM on Gestational Days 12 and 13, 2 hr before phenytoin, 65 mg/kg ip. Other groups were pretreated 2 hr prior to phenytoin administration with either the antioxidant caffeic acid or the free radical spin trapping agent alpha-phenyl-N-t-butylnitrone (PBN). Caffeic acid and PBN were given ip in doses that respectively were up to 1.0 to 0.05 molar equivalents to the dose of phenytoin. Dams were killed on Day 19 and the fetuses were assessed for teratologic anomalies. A similar study evaluated the effect of ASA on the in vivo covalent binding of radiolabeled phenytoin administered on Day 12, in which case dams were killed 24 hr later on Day 13. ASA pretreatment produced a 50% reduction in the incidence of fetal cleft palates induced by phenytoin (p less than 0.05), without significantly altering the incidence of resorptions or mean fetal body weight. Pretreatment with either caffeic acid or PBN resulted in dose-related decreases in the incidence of fetal cleft palates produced by phenytoin, with maximal respective reductions of 71 and 82% at the highest doses of caffeic acid and PBN (p less than 0.05).

• Research Organization: Univ. of Toronto (Canada)
• OSTI ID: 6174102
• Journal Information: Toxicol. Appl. Pharmacol.; (United States), Journal Name: Toxicol. Appl. Pharmacol.; (United States) Vol. 97:2; ISSN TXAPA
• Country of Publication: United States
• Language: English

Related Subjects

550201* -- Biochemistry-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
ACETYLSALICYLIC ACID
ANALGESICS
ANIMALS
ANTICONVULSANTS
ANTIOXIDANTS
ANTIPYRETICS
BIOCHEMICAL REACTION KINETICS
CARBOXYLIC ACIDS
CENTRAL NERVOUS SYSTEM DEPRESSANTS
CHALCOGENIDES
DRUGS
EMBRYOS
ENZYME ACTIVITY
ENZYMES
FETUSES
HYDROXY ACIDS
ISOTOPE APPLICATIONS
ISOTOPES
KINETICS
LABELLED COMPOUNDS
LIGASES
MAMMALS
MICE
NITROGEN COMPOUNDS
NITROGEN OXIDES
ORGANIC ACIDS
ORGANIC COMPOUNDS
OXIDES
OXYGEN COMPOUNDS
PREGNANCY
PROSTAGLANDINS
RADICALS
RADIOISOTOPES
REACTION KINETICS
RODENTS
SENSITIVITY
TERATOGENESIS
TOXICITY
TRACER TECHNIQUES
VERTEBRATES