title: Retinamides: hydrolytic conversion of retinoylglycine to retinoic acid in pregnant mice contributes to teratogenicity.
abstract: Retinamides are prominent among synthetic vitamin A derivatives (retinoids) which can prevent or reduce the incidence of certain carcinogen-induced neoplasms in animals. They also possess lower toxicity toward adult and developmental systems than natural retinoids, presumably because of the presence of an amide endgroup which resists ready hydrolysis. In this investigation, we compared the developmental toxicities in mice of N-(4-hydroxyphenyl)retinamide(4-HPR), N-ethylretinamide (ER) and two retinoylamino acids, N-(all-trans-retinoyl)glycine (RG) and N-(all-trans-retinoyl)-DL-leucine (RL), which are formed from retinoic acid and the alpha-amino acids; RG and RL were shown in a previous study to differ from each other and from retinoic acid in certain toxicity bioassays. We found that while 4-HPR, ER, and RL were only minimally embryotoxic, RG was uniquely active as a teratogen with potency equivalent to that of retinol, the precursor of retinoic acid. Since binding to cytoplasmic proteins and nuclear receptors is a function of the presence of an acidic endgroup in the retinoid molecule, we investigated if RG given to pregnant mice was converted to retinoic acid (RA) and if teratologically significant amounts were detectable in the embryo. A single 100 mg/kg dose of RG in oil vehicle was given orally to ICR mice on day 11 of gestation (plug day = day 0). Extraction and quantification by HPLC of the retinoids in the maternal plasma and in whole embryos were performed at hourly intervals for the first 10 h after dosing and at 26 h. RG was absorbed rapidly reaching peak levels in the maternal plasma at 1 h after the dose and maintained a level of 15 micrograms/mL for up to 4 h, before starting a decline. RG also transferred to the embryo reaching peak levels greater than 0.75 micrograms/g wet weight between 2 and 4 h after the dose. All-trans RA was detected in the maternal plasma and the embryo at 1 h after the dose, reaching peak levels at 2 h in both compartments (0.43 micrograms/mL or g), before starting a decline. Small quantities of 13-cis RG (a contaminant in the original solution comprising 2-3% by weight) and 13-cis RA were also detected in both compartments, but their amounts in the embryo were considered insufficient to contribute to teratogenicity.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Department of Anatomy, Jefferson Medical College, Philadelphia, Pennsylvania 19107.
authors.forename: D M
authors.initials: DM
authors.lastname: Kochhar
authors.forename: Y F
authors.initials: YF
authors.lastname: Shealy
authors.forename: J D
authors.initials: JD
authors.lastname: Penner
authors.forename: H
authors.initials: H
authors.lastname: Jiang
mesh_terms: D000818:Animals; D001681:Biological Assay; D001711:Biotransformation; D002478:Cells, Cultured; D020964:Embryo Loss; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D006868:Hydrolysis; D007930:Leucine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011247:Pregnancy; D013329:Structure-Activity Relationship; D013723:Teratogens / Q000378:metabolism / Q000633:toxicity*; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism / Q000633:toxicity
chemical_list: D013723:Teratogens; C057861:N-retinoylleucine; C057860:N-retinoylglycine; D014212:Tretinoin; D007930:Leucine; D005998:Glycine