sue expresses much lower levels of AHR and ARNT, or has the poor affinity AHR, and the expression and induction of CYP1A1 were lower. A situation emerges in which approximately 350 times fewer receptors are expressed in the human embryo than in the mouse, approximately 200 times more TCDD is required in human embryo tissue than in mouse tissue to produce the critical effects, and the response of a transcriptionally regulated gene (CYP1A1) is approximately 1,500 times lower in human embryo palates than in mouse palates under identical exposure conditions.

Valproic Acid

Valproic acid (VPA) is an anticonvulsant drug used to treat epilepsy with the major side-effect of hepatotoxicity. VPA is unusual in that its human teratogenicity was predicted from laboratory animal studies, without any knowledge of mechanism (Brown et al. 1980; Kao et al. 1981). In all species, including humans, neural-tube-closure defects are a consistent component of the teratogenic effects, but many other organ systems are affected and their sensitivity varies among species (Kao et al. 1981; Robert 1992). The pharmacological effect of VPA appears to involve several mechanisms, including actions on γ-aminobutyric acid (GABA) synthesis and release; the release of γ-hydroxybutyric acid; attenuation of N-methyl-D-aspartate- (NMDA) type glutamate receptors, and direct effects on excitable membranes (Löscher 1999). The mechanisms leading to hepatotoxicity and teratogenicity are distinct and also differ from the pharmacological mechanisms. The exact mechanism of teratogenicity is unclear, but it too might be multifaceted. Suggested actions include effects on the cytoskeleton and cell motility (Walmod et al. 1998, 1999); several aspects of zinc, folate, methionine, homocysteine, and glutathione metabolism (Alonso-Aperte et al. 1999; Hishida and Nau 1998; Bui et al. 1998; Finnell et al. 1997b); peroxisome proliferation-activated receptor δ interaction (Lampen et al. 1999); and gene expression (Wlodarczyk et al. 1996). Despite the initial site of action (“receptor”) being unknown, there is a wealth of information on structure-teratogenicity relationships.

VPA is a simple short-chain carboxylic acid, 2-propylpentanoic acid. The following features affect teratogenicity (Nau 1994): (1) A free carboxylic acid is required. Amides, such as valpromide, are inactive (Spiegelstein et al. 1999; Radatz et al. 1998), as are stable esters. (2) The C2 carbon must be bonded to one hydrogen and two alkyl chains, as well as the carboxyl group. Substituting the hydrogen with any group abolishes activity, and a single chain or unsaturated derivatives (e.g., 2-en-VPA) are also inactive. (3) Activity is greatest when the two alkyl chains are unbranched (Bojic et al. 1996) and contain three carbons (Bojic et al. 1998). (4) Introducing a side-chain double or triple bond terminally (between C3 and C4) enhances teratogenicity but, in any other position, abolishes activity. (5) When one side-chain has a terminal unsaturation, C2 is asymmetric



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