Teratogenicity of isotretinoin revisited: species variation and the role of all-trans-retinoic acid.
This paper reviews the teratogenicity of isotretinoin in regard to aspects of species variation, toxicokinetics, and metabolism. Particular emphasis is given to the hypothesis that most effects of isotretinoin (13-cis-retinoic acid) are mediated by isomerization to the all-trans-retinoic acid. This mechanism of action would provide a basis for the understanding of species differences and the extrapolation of experimental results to the human situation and thus improve drug development. The insensitive species (rat, mouse) eliminate the drug rapidly through detoxification to the beta-glucuronide; also, placental transfer is limited in these species. On the other hand, in sensitive species (primates), the drug is predominantly metabolized to the active 13-cis-4-oxo-retinoic acid; placental transfer is more extensive here. The beta-glucuronides showed limited placental transfer in all species examined; these metabolites exhibited very low, if any, measurable concentrations in the human. The 13-cis-retinoic acid is not appreciably bound to cellular retinoid-binding proteins or nuclear receptors and exhibits low tissue distribution and placental transfer. Its access to the nucleus may be extensive. Because of the long half life of 13-cis-retinoic acid, continuous isomerization results in significant area under the concentration-time curve levels of all-trans-retinoic acid in the mouse, monkey and the human; the all-trans-retinoic acid formed is extensively distributed across the placenta and may be an important factor that contributes to the teratogenic potency of 13-cis-retinoic acid. Isomerization cannot explain the teratogenic effects of 13-cis-retinoic acid in the rat and rabbit. It is concluded that the high teratogenic activity of isotretinoin in sensitive species (human, monkey) is related to slow elimination of the 13-cis-isomer, to metabolism to the 4-oxo-derivative, to increased placental transfer, to continuous isomerization and significant exposure of the target tissue to all-trans-retinoic acid; and to lack of binding to cytoplasmic retinoid binding proteins that could possibly result in ready access to the nucleus.
Nau
H
H
Department of Food Toxicology, School of Veterinary Medicine Hannover, Bischofsholer Damm 15, D-30173 Hannover, Germany. Heinz.Nau@tiho-hannover.de
D000014:Abnormalities, Drug-Induced; D000818:Animals; D003879:Dermatologic Agents / Q000009:adverse effects* / Q000378:metabolism / Q000493:pharmacokinetics; D005260:Female; D006207:Half-Life; D006801:Humans; D007536:Isomerism; D015474:Isotretinoin / Q000009:adverse effects* / Q000378:metabolism / Q000493:pharmacokinetics; D007641:Keratolytic Agents / Q000009:adverse effects*; D008431:Maternal-Fetal Exchange; D051379:Mice; D011247:Pregnancy; D011323:Primates; D011817:Rabbits; D051381:Rats; D013723:Teratogens / Q000378:metabolism / Q000633:toxicity; D014212:Tretinoin / Q000009:adverse effects*
D003879:Dermatologic Agents; D007641:Keratolytic Agents; D013723:Teratogens; D014212:Tretinoin; D015474:Isotretinoin