Arotinoids, which are analogs of
retinoic acid (RA) and
retinol (RO) with the
carbon skeleton in a rigid conformation, have more favorable therapeutic indices relative to all-trans-RA and all-trans-RO. The purpose of this investigation was to obtain preliminary in vivo toxicity data on
SMR-2(analog of RO) and
SMR-6 (analog of RA), arotinoids with promising activity (ED50's of 20 X 10(-11) and 5 X 10(-11) M, respectively; ED50 of RA = 1 X 10(-11) M) for reversal of keratinization in tracheal organ culture. A preliminary toxicity study was conducted in male B6D2F1 mice with gavage of
retinoids in
corn oil (0.01, 0.05, and 0.1 mg/kg/day of
SMR-2 or
SMR-6; 1, 5, and 10 mg/kg/day of RA as reference control). Due to lack of toxicity, each dose level for
SMR-2 and
SMR-6 was increased by 4-fold on Day 29 of dosing. The study was terminated on Day 57.
Hypervitaminosis A (
weight loss,
alopecia, skin scaling, and bone thinning) was induced in the mid- and high-dose SMR groups;
weight-gain depression was predominant in the high-dose RA group. The SMR compounds were approximately 100-fold more toxic, based on
weight loss, than RA. In the SMR dose groups with
hypervitaminosis A, white blood cell counts were elevated 2- to 4-fold; and there were microscopic lesions in skin, testes, epididymis, bone, thymus, bone marrow, peripheral lymph nodes, spleen, stomach, adrenal, and pituitary. The
leukocytosis was attributed to leukopoiesis in spleen and bone marrow, which may be due to either a direct effect and/or a secondary response to a subacute inflammatory reaction in skin. Only peripheral lymph node
hyperplasia was observed in
SMR-2 and RA low-dose groups. Enlarged thymus, lymph node
hyperplasia, leukopoiesis in spleen and bone marrow, elevated
alkaline phosphatase with
bone hypertrophy, and testicular degeneration were observed in the mid-dose RA group. The results indicate that immune stimulation may be a primary early response to
retinoids and that skin, leukopoietic tissues, reproductive organs, stomach, and bone are primary targets for
retinoid toxicity.