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Xenobiotica
the fate of foreign compounds in biological systems
Volume 19, 1989 - Issue 12
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Original Article

Teratogenicity of phenylhydantoins in an in vitro system: Molecular orbital-generated quantitative structure-toxicity relationships

, , , &
Pages 1471-1481 | Received 21 Jul 1988, Accepted 16 Aug 1989, Published online: 30 Sep 2009
 

Abstract

1. The ability of 20 mono- and di-phenylhydantoin derivatives to inhibit differentiation of rat embryo mid-brain and limb bud cells in culture has been used as an index of the teratogenic hazard represented by these compounds.

2. Molecular orbital calculations on these compounds, using the MINDO-3 (modified intermediate neglect of differential overlap) and CNDO-2 (complete neglect of differential overlap) methods, were combined with indices of teratogenicity in the two cell types, to generate a coherent structure-toxicity relationship.

3. Teratogenicity correlated with frontier orbital electron density of the N1 hydantion ring atom (HOMO-N1) in a sub-series of 12 monophenylhydantions, whereas the corresponding toxicity for both mono- and di-phenylhydantoins related more to the molecular polarizability (αmol) of the molecule.

4. Furthermore the same structural parameter (αmol) exhibited a parallelism with log P values of these 20 compounds, indicating the importance of lipophilicity in the toxicity of these compounds.

5. Overall, the data emphasize the ability of electronic structural calculations to identity chemical descriptors of toxicity.

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