Teratogenic metabolites

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. 

Oxfendazole may be administered orally or intraruminally to cattle and sheep for treatment and control of roundworms and tapeworms at a dosage of 4.5 mg/kg bw. Oxfendazole, although teratogenic per se in sheep, does not produce teratogenic metabolites. 

Aflatoxins are potent carcinogenic, mutagenic and teratogenic metabolites produced by molds. The major food affected with aflatoxins are corn, peanuts, rice, cottonseeds, dried fruit and milk from ingestion (103). The US action standards established by FDA are 20 pg/Kg for foods consumed by humans and 0.5 pg/kg for milk. In the case of animal feed, the levels are from 100 to 300 pg/kg. Therefore, assays capable of detecting at these levels have to be developed, (see Table 1 (104,105)). Detection of aflatoxins entails conjugation of these small molecules with carrier proteins like bovine serum albumin to produce antibodies (20). A number of commercial kits for aflatoxins are available (see sections on kits and immunoaflinity purification). 

Cyclophosphamide requires metabolic activation to form the teratogenic metabolites, phosphoramide mustard, and acrolein (Figure 34.5). The former metabolite produces single-stranded DNA breaks, DNA-DNA and DNA-protein crosslinking. In contrast, acrolein preferentially binds to proteins, and it concentrates in the... 

Reist, M., Carrupt, P. A., Erancotte, E., Testa, B. Chiral inversion and hydrolysis of thalidomide mechanisms and catalysis by bases and serum albumin, and chiral stability of teratogenic metabolites. Chem. Res. Toxicol. 1998, 11, 1521-1528. 

After intraamniotic injection, acrolein is teratogenic to rats in vivo but not in vitro. When administered intraamniotically to the whole embryo culture system of the rat on day 13 of gestation, acrolein caused edema, hydrocephaly, open eyes, cleft palate, abnormal umbilical cord, and defects of the limbs and face (Slott and Hales 1986). Beauchamp etal. (1985) suggest that acrolein-associated teratogenicity is caused by acrylic acid, an acrolein metabolite. Acrylic acid injected into amniotic fluid of rats on day 13 of gestation produced a dose-dependent increase in the percent of fetuses with skeletal and other abnormalities (Beauchamp et al. 1985). 

Metabolites 4.203 and 4.205 were minor. Metabolite 4.204 was the main product in rats and dogs. Toxicological investigations revealed that, of the twelve hydrolysis products of thalidomide, only the three containing the intact phthalimido moiety show teratogenic activity, namely metabolites 4.202, 4.203, and 4.205) [132] [133],... 

Developmental Toxicity. It is not known whether 1,2-diphenylhydrazine crosses the placenta, but there is no reason to assume that it (or its metabolites) would not do so. Developmental studies in mammals would provide information on possible fetotoxic and teratogenic effects of... 

Fig. 8.1 Structures of thalidomide, EM-12 and their metabolites which are all angiogenesis inhibitors and teratogens or potential teratogens.

---