Teratogenicity, tissue distribution, and metabolism of the retro-retinoids, 14-hydroxy-4,14-retro-retinol and anhydroretinol, in the C57BL/6J mouse.
The retro-retinoids 14-hydroxy-4,14-retro-retinol (14-HRR) and anhydroretinol (AR) are endogenous metabolites of retinol (Vitamin A). 14-HRR and retinol, but not retinoic acid, promote the proliferation of lymphocytes and fibroblasts when cultured in serum-free medium, whereas AR competitively inhibits these growth-supportive effects. Retinol and all-trans-retinoic acid are potent teratogens. This study shows the teratogenic potencies of 14-HRR and AR compared to retinol at a single gestational time. Also reported is the metabolism of these retinoids in nonpregnant mouse liver, the primary storage tissue of vitamin A, where many retinoids will be present at their highest concentration. Additionally, measurement of these metabolite concentrations was carried out in pregnant mouse plasma and embryos because they are the most relevant to teratology. Single intraperitoneal administration of 60 mg/kg of all-trans-retinol (retinol) to C57BL/6J mice at gestational day 7.5 produced a significant induction of eye and axial skeletal malformations. The equivalent dose of 14-HRR or AR induced a lower frequency of embryolethality and eye and axial skeletal malformations indicating that these retro-retinoids are less potent teratogens than retinol. The distribution of 14-HRR, AR, retinol, and their metabolites was determined in the liver at a single time point after retinoid administration. Two hours after 60 mg/kg of 14-HRR treatment, HRR esters are detected. Two hours after 600 mg/kg of AR treatment, 14-HRR is detected, suggesting that 14-HRR, a reported metabolite of retinol, can be biosynthesized from AR. In both cases, neither retinoic acid nor retro-retinoid acidic metabolites were detected. Two hours after 60 mg/kg of retinol treatment, 14-HRR, 13,14-dihydroxyretinol (DHR), AR, and retinoic acid were detected. A new endogenous retro-retinoid, to which the 4-hydro-5-hydroxy-anhydroretinol structure is proposed, was detected in all liver extracts. Retinoic acid, 14-HRR, and DHR were present in plasma and embryos of retinol-treated pregnant mice. Plasma and embryos of AR-treated pregnant mice contained 14-HRR and AR, but the retinoic acid concentration did not increase compared to controls. In summary, the retro-retinoids 14-HRR and AR are weaker teratogens than retinol. The low teratogenicity observed might be due to the facts that 14-HRR and AR do not contain the terminal carboxylic group involved in binding and activation of the retinoic acid nuclear receptors and they are not metabolized to acidic retinoids.
Mao
G E
GE
Department of Environmental Health Sciences, School of Public Health, Los Angeles, California, 90095, USA.
Collins
M D
MD
Derguini
F
F
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000818:Animals; D001667:Binding, Competitive; D004224:Diterpenes; D004305:Dose-Response Relationship, Drug; D005124:Eye Abnormalities / Q000139:chemically induced; D005260:Female; D007274:Injections, Intraperitoneal; D008099:Liver / Q000196:embryology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D014018:Tissue Distribution; D014801:Vitamin A / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity
D004224:Diterpenes; D014801:Vitamin A; C072014:14-hydroxy-4,14-retro-retinol; C031469:anhydrovitamin A