Teratogenesis metabolism

In addition to direct effects of chemical compounds on the fetus, metabolic disturbances in the mother, such as diabetes or hyperthermia, or deficiencies of calories or specific nutrients such as vitamin A, zinc, and folic acid may lead to teratogenesis. Compounds that inhibit placental functions may also induce malformations, e.g., by inhibiting placental circulation. For example, hydroxyurea disrupts the placental circulation and induces malformations. In addition, it also induces DNA damage. 

Arnhold, T, Ehnazar, M.M.A., and Nau, H., Prevention of vitamin A teratogenesis by phytol or phytanic acid results from reduced metabolism of retinol to the teratogenic metabolite, all frara-retinoic acid, Toxicol. Sci., 66, 274, 2002. 

Fort, D.J., B.L. James, and J.A. Bantle. 1989. Evaluation of the developmental toxicity of five compounds with the frog embryo teratogenesis assay Xenopus (FETAX) and a metabolic activation system. Jour. Appl. Toxicol. 9 377-388. 

Ellison, A.C. and Maren, T.H. (1972). The effect of potassium metabolism on acetazolamide-induced teratogenesis. Johns Hopkins Med. J. 130 105-115. 

Weaver, T.E. and Scott, W.J. (1984b). Acetazolamide teratogenesis Interaction of maternal metabolic and respiratory acidosis in the induction of ectrodactyly in C57B1/6J mice. Teratology 30 195-202. 

Primary hepatocyte cultures have been used in vitro to metabolically activate toxins for evaluation with target tissues. Cocultures of rat embryos with hepatocytes have been used to study the role of metabolism in teratogenesis (Oglesby et al., 1986). Lindahl-Kiessling et al., (1989), in an attempt to bring test conditions closer to in vivo conditions, developed an assay utilizing primary rat hepatocytes and human peripheral lymphocytes to detect metabolism-mediated mutagenesis. 

Fort DJ et al (1998) Phase III interlaboratory study of FETAX, Part 2 interlaboratory validation of an exogenous metabolic activation system for frog embryo teratogenesis assay-Xenopus (FETAX). Drug Chem Toxicol 21(1) 1-14... 

Nau H (1987) Species differences in pharmacokinetics, drug metabolism and teratogenesis. In Nau H Scott WJ Jr ed. Pharmacokinetics in teratogenesis, Vol. 1. Boca Raton, Florida, CRC Press, pp 81-106. 

The two most serious toxic effects of valproic acid are hepatocellular injury (96) and teratogenesis (97). Since CYP2A6 and CYP2C9 are known to oxidize valproic acid to a 4-ene metabolite that is hepatotoxic, inducers of these isoforms, including other antiepileptic agents, are likely to increase the risk of hepatotoxicity (98). However, valproic acid also is metabolized by several other pathways that may be involved in causing its toxicities (99). 

Shum, S., N.M. Jensen, and D.W. Nebert. The Murine Ah locus In utero toxicity and teratogenesis associated with genetic differences in benzo(a)pyrene metabolism. Teratology 20 365-376, 1979. 

Figure 34.5. Metabolic pathway for the bioactivation of cyclophosphamide. (Adapted from Mirkes,P. E. Cyclophosphamide teratogenesis A review. Teratog. Carcinog. Mutagen. 5,75-88, 1985.)...

Fort, D.J., E.L. Stover, J.A. Bantle, J.R. Rayburn, M.A. Hull, R.A. Finch, D.T. Burton, S.D. Turley, D.A. Dawson, G. Linder, D. Buchwalter, M. Kumsher-King, and A.M. Gaudet-Hull. 1998. Phase III interlaboratory study of FETAX, Part 2 Interlaboratory validation of an exogenous metabolic activation system for frog embryo teratogenesis assay-Xenopus (FETAX). Drug Chem. Toxicol. 21(1) 1-14. 

Approximately 7% of all live-born humans bear birth defects. This value may be as high as 10% if children are evaluated to age 10 years to include subtle structural or functional deficits such as minimal brain dysfunction or attention deficit disorders. More than 560 000 lives out of 3 million births per year in the United States are lost through infant death, spontaneous abortion, stillbirths, and miscarriage due presumably to defective fetal development. The relative contributions to human teratogenesis have been estimated as follows known germinal mutations, 20% chromosomal and gene aberrations, 3-5% environmental causes such as radiation, <1% infections, 2% or 3% maternal metabolic imbalance, 1% or 2% drugs and environmental chemicals, 4% or 5% contributions from maternal dietary deficiencies or excesses and... 

The study of xenobiotic metabolism has developed rapidly during the past few decades. These studies have been fundamental in the assessment of drug efficacy, safety, and design of dosage regimens in the development of food additives and the assessment of potential hazards of contaminants in the evaluation of toxic chemicals and in the development of pesticides and herbicides and their metabolic fate in insects, other animals, and plants. The metabolism of many xenobiotics is fundamental to many toxic processes such as carcinogenesis, teratogenesis, and tissue necrosis. Often the same enzymes involved in... 

Thcfrojj embryo teratogenesis assay (FETAX) is a similar ex vivo test based on a Xenopus laevis model. Fertilized eggs in the mid- to late-blastula stage are exposed to test compounds and scored for lethality, growth retardation, and malformations. An interlaboratory validation study with 12 compounds [13], including a metabolic activation system, provided repeatable data, and a recent publication from a pharma industry reported very positive results testing over 400 chemicals with 81 % predictivity and a minimal proportion of false-positive compounds [14]. 

Diphenylhydantoin. An anticonvulsant drug causing orofacial (cleft palate) and skeletal malformations, especially on days 11-12 in mice. Teratogenesis shows a steep dose-response. The mechanism may involve metabolism (epoxidation) and covalent binding to protein. 

Racemic 188-HC1 was found to be highly toxic and teratogenic in a frog embryo teratogenesis assay. The potency was increased with a cytochrome P-450 metabolic activation system [467],... 

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