The Role of Metabolism and Toxicokinetics in Retinoid Teratogenesis

Abstract

Retinoids (vitamin A and its analogs) exert profound effects on a wide variety of life processes, including morphogenesis and embryonic development. Several retinoids are also effective drugs for therapy of skin diseases and some types of cancer. However, the applicability of this class of compounds is limited by their teratogenic activity. A major question in retinoid toxicology has been the marked interspecies differences in the lowest teratogenic doses of 13-cis-retinoic acid and retinol. In addition, great attention has been drawn to the risk assessment of embryotoxicity resulting from excessive intake of vitamin A by pregnant women. The present review first gives an overview of the biochemistry, metabolism and mode of action of retinoids as well as their role in embryonic development. It then summarizes the results of recent studies on retinoid metabolism, toxicokinetics, and embryonic exposure and discusses how the available information provides explanation of the aforementioned interspecies variations. Finally, it presents some approaches for risk assessment of high vitamin A intake by humans based on various animal models and epidemiological studies.

Concentrations of retinoids in early pregnancy and in newborns and their mothers

“…Probably, the teratogenic effects are exerted mainly by way of all-trans retinoic acid (9), although 13-cis retinoic acid and its metabolite 4-oxo-13-cis retinoic acid also may have teratogenic effects (5,16). The exact roles of the various derivatives are difficult to evaluate, because all-trans retinoic acid can isomerize to 13-cis retinoic acid, and this reaction is reversible (3).…”

“…In insensitive species, retinoic acids are glucuronidated to retinoyl-␤-glucoronide (8,16). This process leads to low placental transfer of 13-cis retinoic acid into embryonic tissues, because retinoyl-␤-glucoronide shows limited placental transfer (5).…”

“…This process leads to low placental transfer of 13-cis retinoic acid into embryonic tissues, because retinoyl-␤-glucoronide shows limited placental transfer (5). However, in sensitive species, 13-cis retinoic acid has a slower metabolism to the active 4-oxo-13-cis retinoic acid, which also has a higher degree of placental transfer (3,16). Humans belong to the sensitive species.…”

Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

“…All-trans-retinoic acid is involved in gene transcription, cell division, and differentiation (Tzimas and Nau, 2001;Marill et al, 2003;Duester, 2008). According to more recent data, however, CYP26A1 and CYP3A4 are the primary determinants of all-trans-retinoic acid metabolism in humans, whereas the role of CYP2C8 is of smaller importance (Thatcher et al, 2010).…”

Potentiation of the teratogenic effects induced by coadministration of retinoic acid or phytanic acid/phytol with synthetic retinoid receptor ligands

“…Other interactions with ROH-induced teratogenesis may also be important (Santos-Guzman et al 2003). Additional interactions are expected because of the complex metabolic scheme of vitamin A/retinoids (Tzimas and Nau 2001). …”