Lindamood C, Giles H D, Hill D L
Fundam Appl Toxicol. 1987 May;8(4):517-30. doi: 10.1016/0272-0590(87)90137-0.
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.
芳香维甲酸类化合物是视黄酸（RA）和视黄醇（RO）的类似物，其碳骨架呈刚性构象，相对于全反式视黄酸和全反式视黄醇具有更有利的治疗指数。本研究的目的是获得关于SMR - 2（视黄醇类似物）和SMR - 6（视黄酸类似物）的初步体内毒性数据，这两种芳香维甲酸类化合物具有有望逆转气管器官培养中角化的活性（ED50分别为20×10⁻¹¹和5×10⁻¹¹ M；视黄酸的ED50 = 1×10⁻¹¹ M）。在雄性B6D2F1小鼠中进行了一项初步毒性研究，通过玉米油灌胃给予类维生素A（SMR - 2或SMR - 6，剂量分别为0.01、0.05和0.1 mg/kg/天；视黄酸作为参考对照，剂量为1、5和10 mg/kg/天）。由于未观察到毒性，在给药第29天，将SMR - 2和SMR - 6的每个剂量水平提高了4倍。该研究在第57天终止。中剂量和高剂量SMR组诱导了维生素A过多症（体重减轻、脱发、皮肤脱屑和骨质变薄）；高剂量视黄酸组主要表现为体重增加抑制。基于体重减轻，SMR化合物的毒性比视黄酸大约高100倍。在出现维生素A过多症的SMR剂量组中，白细胞计数升高了2至4倍；皮肤、睾丸、附睾、骨骼、胸腺、骨髓、外周淋巴结、脾脏、胃、肾上腺和垂体出现了微观病变。白细胞增多归因于脾脏和骨髓中的白细胞生成，这可能是由于对皮肤亚急性炎症反应的直接作用和/或继发反应。在SMR - 2和视黄酸低剂量组中仅观察到外周淋巴结增生。中剂量视黄酸组观察到胸腺肿大、淋巴结增生、脾脏和骨髓中的白细胞生成、碱性磷酸酶升高伴骨质肥大以及睾丸变性。结果表明，免疫刺激可能是对类维生素A的主要早期反应，并且皮肤、白细胞生成组织、生殖器官、胃和骨骼是类维生素A毒性的主要靶器官。
