Murine toxicology and pharmacology of UAB-8, a conformationally constrained analog of retinoic acid.

Academic Article

Abstract

  • (2E, 4E, 6E)-8-[3'-Ethyl-2'-(1-methylethyl)-2'-cyclohexen-1'-ylidene] -3, 7-dimethyl-2,4,6-octatrienoic acid (UAB-8) has potent activity in preventing papillomas on the skin of mice similar to that determined in a previous study for the homolog containing one less carbon atom. To evaluate the toxicological profile for UAB-8, relative to all-trans-retinoic acid (RA), female mice were dosed by oral gavage for 29 days with amounts of 0.05, 0.1, or 0.2 mmol/kg/day. For the two compounds, the effects on body weights were similar. Mice dosed with UAB-8, however, had a lower incidence of clinical signs of toxicity (alopecia, scaly skin, and limping). At necropsy, bone fractures, skin abnormalities, and splenomegaly were observed in some mice dosed with RA but not in any dosed with UAB-8. Lymph node hyperplasia was noted in some mice dosed with either dose of RA but only in those dosed with the highest dose of UAB-8. All dose levels of RA produced microscopic lesions in the bones of mice; only the highest dose of UAB-8 had this effect. RA and UAB-8 had similar effects on chondrogenesis in cultures of cells from mouse limb buds, an indication of comparable teratogenic effects. For mice dosed i.v. (10 mg/kg), there was a saturated phase of elimination of RA from plasma (Km = 0.61 microgram/ml and Vmax = 2572 micrograms/hr); no such phase was noted when UAB-8 was administered. UAB-8 had values for t1/2 alpha and t1/2 beta of 0.47 and 17.1 hr, respectively. Relative to RA, UAB-8 has a favorable toxicological profile and different pharmacokinetics.
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    Keywords

  • Animals, Body Weight, Calcification, Physiologic, Erythrocyte Count, Female, Hematocrit, Hemoglobins, Keratolytic Agents, Limb Buds, Lymph Nodes, Mice, Papilloma, Skin, Skin Neoplasms, Tretinoin
  • Digital Object Identifier (doi)

    Authorlist

  • Lin TH; Rogers TS; Hill DL; Simpson-Herren L; Farnell DR; Kochhar DM; Alam M; Brouillette WJ; Muccio DD
  • Start Page

  • 310
  • End Page

  • 316
  • Volume

  • 139
  • Issue

  • 2