Hough S, Avioli L V, Muir H, Gelderblom D, Jenkins G, Kurasi H, Slatopolsky E, Bergfeld M A, Teitelbaum S L
Department of Medicine, Stellenbosch University School of Medicine, Tygerberg, South Africa.
Endocrinology. 1988 Jun;122(6):2933-9. doi: 10.1210/endo-122-6-2933.
Vitamin A toxicity has been associated with alterations in mineral metabolism and may result in osteopenia, fractures, deformities, and growth arrest. The pathogenesis of the bone lesions that occur in vitamin A toxicity is, however, ill defined and was examined in the present study. The administration of pharmacological doses of vitamin A to growing male rats resulted in weakness and spontaneous fractures. Undecalcified bone histology of vitamin A toxic animals was characterized by increased bone resorption, osteoclastosis, a paucity of trabecular surfaces covered with osteoid, and lesions which appear to be pathognomonic of hypervitaminosis A. The serum calcium and magnesium levels of vitamin A-toxic animals were unremarkable, but serum phosphate levels were significantly higher than control values. Urinary hydroxyproline excretion reflected bone histology and was significantly increased in experimental rats. Circulating levels of the potent bone resorbers, PTH, 1,25-dihydroxyvitamin D, and 25-hydroxyvitamin D, were, however, comparable in vitamin A-toxic and control animals, suggesting a possible direct effect of vitamin A on bone. Subsequently, the effects of vitamin A (retinol) on in vitro collagen synthesis (incorporation of [3H]proline into collagen) and bone resorption (45Ca release from bone) were examined using a fetal rat calvarial culture. Retinol added to the culture medium for 20-24 h in concentrations ranging from 0.5-10 micrograms/ml selectively inhibited collagen synthesis in a dose-dependent fashion. Higher concentrations of retinol were toxic and resulted in a general inhibition of protein synthesis. Bone resorption was stimulated by 0.5 and 2.5 micrograms/ml retinol. We conclude that vitamin A toxicity in rats causes bone lesions, the genesis of which can be explained, at least in part, by a direct effect of the vitamin on skeletal tissue.
维生素A毒性与矿物质代谢改变有关，可能导致骨质减少、骨折、畸形和生长停滞。然而，维生素A毒性中发生的骨病变的发病机制尚不明确，本研究对此进行了探讨。给生长中的雄性大鼠服用药理剂量的维生素A会导致虚弱和自发性骨折。维生素A中毒动物的未脱钙骨组织学特征为骨吸收增加、破骨细胞增多、覆盖类骨质的小梁表面稀少，以及出现似乎是维生素A过多症的特征性病变。维生素A中毒动物的血清钙和镁水平无明显异常，但血清磷水平明显高于对照值。尿羟脯氨酸排泄反映了骨组织学情况，在实验大鼠中显著增加。然而，强效骨吸收剂甲状旁腺激素（PTH）、1,25-二羟维生素D和25-羟维生素D的循环水平在维生素A中毒动物和对照动物中相当，提示维生素A可能对骨骼有直接作用。随后，使用胎鼠颅骨培养物研究了维生素A（视黄醇）对体外胶原合成（[3H]脯氨酸掺入胶原）和骨吸收（骨中45Ca释放）的影响。在培养基中添加浓度为0.5 - 10微克/毫升的视黄醇20 - 24小时，以剂量依赖方式选择性抑制胶原合成。更高浓度的视黄醇具有毒性，导致蛋白质合成普遍受到抑制。0.5和2.5微克/毫升的视黄醇刺激骨吸收。我们得出结论，大鼠维生素A毒性会导致骨病变，其发生至少部分可由维生素对骨骼组织的直接作用来解释。
