Protection by free oxygen radical scavenging enzymes against salicylate-induced embryonic malformations in vitro.
Salicylates are among the oldest and most widely used drugs and are known to lead to foetal death, growth retardation and congenital abnormalities in experimental animals. In this study, the effects of acetyl salicylic acid (ASA), salicylic acid (SAL) and sodium salicylate (NaSAL) on early organogenesis and the interaction of these molecules with free radicals has been investigated. Postimplantation rat embryos were cultured in vitro from day 9.5 of gestation for 48 hr. ASA, SAL and NaSAL were added to whole rat serum at concentrations between 0.1 and 0.6 mg/ml. Also, the lowest effective concentration of ASA for all parameters (0.3 mg/ml) and the same concentration of NaSAL and SAL was added to the culture media in the presence of superoxide dismutase (SOD) (30 U/ml) or glutathione (0.5 micromol/ml). The growth and development of embryos was compared and each embryo was evaluated for the presence of any malformations. When compared to growth of control embryos, the salicylates decreased all growth and developmental parameters in a concentration-responsive manner. There was also a concentration-related increase in overall dysmorphology, including the incidence of haematoma in the yolk sac and neural system, open neural tube, abnormal tail torsion and the absence of fore limb bud. When SOD was added in the presence of ASA, growth and developmental parameters were improved and there was a significant decrease in the incidence of malformations. Addition of SOD also decreased the incidence of malformations in the presence of SAL, but did not effect the growth and developmental parameters of SAL and NaSAL. There was no significant difference between the embryos grown in the presence of these three molecules on the addition of glutathione. The effects of salicylates might involve free oxygen radicals by the non-enzymatic production of the highly teratogenic metabolites 2,3- and 2,5-dihydroxybenzoic acid. An enhanced production of these metabolites in embryonic tissues may be directly related to the increased risk of congenital malformations.
Karabulut
A K
AK
Department of Anatomy, Faculty of Medicine, Selcuk University, Konya, Turkey. akkarabulut@yahoo.com
Ulger
H
H
Pratten
M K
MK
D000014:Abnormalities, Drug-Induced / Q000517:prevention & control*; D000818:Animals; D001241:Aspirin / Q000633:toxicity*; D004347:Drug Interactions; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D005260:Female; D016166:Free Radical Scavengers / Q000378:metabolism / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D009924:Organ Culture Techniques; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D020156:Salicylic Acid / Q000633:toxicity*; D012980:Sodium Salicylate / Q000633:toxicity*; D013482:Superoxide Dismutase / Q000378:metabolism / Q000494:pharmacology*
D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D005978:Glutathione; D020156:Salicylic Acid; D001241:Aspirin; D012980:Sodium Salicylate