Chemical structure--teratogenicity relationships, toxicokinetics and metabolism in risk assessment of retinoids

Toxicology Letters
H Nau

Abstract

Retinoic acid, an oxidative metabolite of vitamin A, is involved in the control of many biological processes including embryonic development and excess as well as deficiency of retinoids has been found to be teratogenic. The effects of retinoids in normal as well as abnormal development may be mediated by two members of retinoid receptors, the RARs and RXRs, which exhibit specific temporal and spatial expression during development. Evidence accumulates that any alteration of this complex retinoid system may be related to teratogenic effects. Here we investigate the influence of toxicokinetic parameters, including aspects of metabolism and placental transfer, on the teratogenic potency of retinoids. It is demonstrated that activation (oxidation of retinoic acids; hydrolysis of glycoconjugates) and deactivation reactions (isomerization from trans- into cis-configuration; beta-glucuronidation) relate to teratogenesis. The beta-glucuronides of retinoic acids show poor placental transfer and prolonged presence in the maternal organism. Non-retinoid compounds such as antiepileptic agents may exert some of their teratogenicity via alteration of endogenous retinoid levels.

References

Jun 1, 1986·Teratology·F W RosaF O Kelsey
Feb 1, 1994·Nutrition Reviews·M Maden

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Citations

Feb 7, 1998·Reproductive Toxicology·R K MillerU W Wiegand
May 20, 1999·Annual Review of Pharmacology and Toxicology·M D Collins, G E Mao
Jun 15, 2000·Environmental Health Perspectives·E A London
Jul 19, 2001·Arquivos de neuro-psiquiatria·N S MarchiW A Tognola
Jun 16, 2007·Birth Defects Research. Part B, Developmental and Reproductive Toxicology·Mildred S ChristianLouise Latriano

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