Abstract
Repeated ingestion of high doses of retinoids cause the so-called hypervitaminosis A syndrome. In rats the main symptoms are weight loss, alopecia, erythema, desquamation of the skin, and alterations of the skeletal system, including bone fractures. In the present study, three retinoids (Ro 15-1570, arotinoid ethylsulfone, 6 mg/kg; retinoic acid, 100 mg/kg and etretinate, 50 mg/kg) were administered orally to rats for 1 and 2 weeks, respectively, to six male and six female rats/group. All the above changes were induced by all three retinoids, with the exception that the arotinoid ethylsulfone Ro 15-1570 did not cause bone alterations. The absence of toxic effects on the bones by Ro 15-1570 was confirmed by X-ray-film examinations, densitometry of the X-rayed femora and tibiae, examination of the thickness of the femoral and tibial compacta in histological slides plus the determination of the femoral ash weight and its main inorganic constituents (calcium, magnesium, sodium, and potassium). The present demonstration that the arotinoid ethylsulfone Ro 15-1570 was devoid of bone toxicity constitutes major progress in the pharmacologic development of retinoids with a better balance between therapeutic and adverse effects.
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References
Bollag W (1979) Retinoids and cancer. Cancer Chemother Pharmacol 3: 207–215
Bollag W (1981) Arotinoids. A new class of retinoids with activities in oncology and dermatology. Cancer Chemother Pharmacol 7: 27–29
Bollag W (1983) Vitamin A and retinoids: from nutrition to pharmacotherapy in dermatology and oncology. Lancet, pp 860–863
Breitman TR, Selonik SE, Collins SJ (1980) Induction of differentiation of the human promyelocytic leukemia cell line (HL-60) by retinoic acid. Proc Natl Acad Sci USA 77: 2936–2940
Dämmrich K (1970) Zur formalen Pathogenese der Systemerkrankungen des Skeletts bei Tieren. Berl Münch Tierärztl Wschr 83: 106–112
Gallandre F, Kistler A, Galli B (1980) Inhibition and reversion of chondrogenesis by retinoic acid in rat limb bud cell cultures. Wilhelm Roux's Arch 189: 25–33
Hixson EJ, Denine EP (1978) Comparative subacute toxicity of all-trans- and 13-cis-retinoic acid in Swiss mice. Toxicol Appl Pharmacol 44: 29–40
Kistler A (1978) Inhibition of vitamin A action in rat bone cultures by inhibitors of RNA and protein synthesis. Experientia 34: 1159–1161
Kistler A (1981) Structure-activity relationship of retinoids in fetal rat bone cultures. Calcif Tissue Int 33: 249–254
Kistler A (1982) Retinoic acid-induced cartilage resorption. Induction of specific changes in protein synthesis and inhibition by tunicamycin. Differentiation 21: 168–174
Klaus M, Bollag W, Huber P, Küng W (1983) Sulfur-containing arotinoids. A new class of retinoids. Eur J Med Chem 18: 425–429
Leelaprute V, Boonpucknavig V, Bhamarapravati N, Weerapradist W (1973) Hypervitaminosis A in rats. Arch Pathol 96: 5–9
Lewis CA, Pratt RM, Pennypacker JP, Hassell JR (1978) Inhibition of limb chondrogenesis in vitro by vitamin A: Alterations in cell surface characteristics. Dev Biol 64: 31–47
Loeliger P, Bollag W, Mayer H (1980) Arotinoids, a new class of highly active retinoids. Eur J Med Chem 15: 9–15
Moore T (1967) Effects of vitamin A deficiency in animals. Pharmacology and toxicology of vitamin A. In: Sebrell WH and Harris RS (eds) The Vitamins, vol I. Academic Press, New York, pp 245–266
Peck GL (1981) Retinoids in clinical dermatology. In: Fleischmajer R (ed) Progress in diseases of the skin, vol 1. Grune and Stratton, New York, pp 227–269
Peck GL (1983) Retinoids: therapeutic use in dermatology. Curr Ther 24: 103–112
Sidell N (1982) Retinoic acid-induced growth inhibition and morphologic differentiation of human neuroblastoma cells in vitro. J Natl Cancer Inst 68: 589–593
Sterz H, Saackel L (1977) Automated television scanning technique for the quantitative evaluation of X-ray shadows of individual bones. In: Neubert D, Merker HJ and Kwasigroch TEW (eds) Methods in prenatal toxicology. G Thieme Publishers, Stuttgart, pp 362–370
Strickland S, Mahdavi V (1978) The induction of differentiation in teratocarcinoma stem cells by retinoic acid. Cell 15: 393–404
Studer A (1950) Zur Wirkung großer Dosen von Vitamin A im Tierexperiment. Schw Z Allg Pathol Bakteriol 13: 799–802
Studer A, Zbinden G, Uehlinger E (1962) Hypervitaminosis A. In: Büchner F, Letterer E and Roulet F (eds) Handbuch der Allgemeinen Pathologie, vol 2. Springer-Verlag, Berlin-Göttingen-Heidelberg, pp 963–976
Teelmann K (1981) Experimental toxicology of the aromatic retinoid Ro 10-9359 (etretinate). In: Orfanos CE, Braun-Falco O, Farber EM, Grupper C, Polano MK and Schuppli R (eds) Retinoids. Springer-Verlag, New York, pp 41–47
Teelmann K (1983) Comparative toxicity of oral all-trans-retinoic acid and the aromatic retinoids Ro 10-9359 and Ro 12-7554 in rats: hematologic and biochemical studies. Drug Dev Res 3: 49–57
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Kistler, A., Sterz, H. & Teelmann, K. Ro 15-1570, a new sulfur-containing retinoid devoid of bone toxicity in rats. Arch Toxicol 56, 117–122 (1984). https://doi.org/10.1007/BF00349083
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DOI: https://doi.org/10.1007/BF00349083