Phenytoin, teratogenesis

DNA repair is deficient are more susceptible to these reactions (115). Therefore, although the exact changes in macromolecular structure and function responsible for phenytoin teratogenesis remain to be identified, it is likely that DNA damage plays a critical role in much the same way as has been described for carcinogenic reactions. 

The potential ability of fluconazole to modulate pheny-toin teratogenesis has been studied in Swiss mice (59). Pretreatment with a non-embryotoxic dosage of fluconazole (10 mg) potentiated phenytoin teratogenesis combined treatment of fluconazole 50 mg with phenytoin resulted in a significant increase in embryo deaths. The mechanism of this teratological interaction remains to be established. 

LENZ, W. (1965) Epidemiology of congenital malformations. Ann. N.Y. Acad. Sci., 123,128. MARTZ, F., FAILINGER, C. and BLAKE, D.A. (1977) Phenytoin teratogenesis correlation between embryopathic effect and covalent binding of a putative arene oxide metabolite in gestational tissue. J.Pharmac. Exp. Ther., 203, 321. 

Watkinson, W.P. and Millicovsky, G. (1983). Effect of phenytoin on maternal heart rate in A/J mice Possible role in teratogenesis. Teratology 28 1-8. 

There is evidence that phenytoin is teratogenic in humans, but the mechanism is not clear. However, it is known that phenytoin can produce a folate deficiency, and folate deficiency is associated with teratogenesis. 

Choice of drug is also determined by the patient s age and sex. This is particularly true for women who prefer to avoid drugs associated with teratogenesis or that have adverse effects on their appearance, e.g. hirsutism from phenytoin. 

A final remarkable feature of teratogenesis is the dramatic species- and strain-dependent variability in susceptibility for some xenobiotics. For example, some strains of mice are sensitive to phenytoin teratogenicity, while other strains are resistant. In the case of thalidomide, primates (including humans) and rabbits are sensitive, while all rodent (mice and rats) strains tested are resistant. These differences must be considered in the design and interpretation of data from animal studies when directed towards an evaluation of human risk. 

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