1,25(OH)2D3 receptors and endorgan response in experimental aluminium intoxication.
Severe aluminium-induced osteomalacia is refractory to treatment with 1,25(OH)2D3 which frequently causes hypercalcemia. To further explore the mechanisms involved, we have utilized a model of short-term aluminium intoxication in the rat (total: 11 mg elemental aluminium in 3 weeks) to study (a) 1,25(OH)2D3 receptor status in a variety of classical and non-classical target organs for 1,25(OH)2D3; (b) circulating 1,25(OH)2D3 levels; (c) baseline duodenal calcium transport, utilising the Ussing chamber, to investigate the functional significance of receptor status in a classical target organ; and (d) duodenal calcium transport response to exogenously administered 1,25(OH)2D3. Both in the three week model and in the 16 week model (total: 41 mg elemental calcium) increased maximal specific binding capacity for 1,25(OH)2D3 (Nmax), that is, number of unoccupied receptors, was observed in nuclear fractions of all tissues studied. Receptor affinity, the apparent dissociation constant KD, was unchanged. Total binding capacity, measured after displacement of endogenous ligand by Mersalyl, that is, the sum of occupied plus non-occupied receptors, was also increased. Both circulating 1,25(OH)2D3, mucosa-to-serosa calcium flux (Jms) and net calcium flux (Jnet) were reduced under baseline conditions, suggesting the lack of a direct relationship between receptor expression and endorgan response. Following exogenous 1,25(OH)2D3 administration, calcium Jms and Jnet were significantly lower in the aluminium intoxicated animals, with the increment induced in Jnet in aluminium intoxicated animals being 63% of that induced in controls. Our data suggest that resistance to the action of 1,25(OH)2D3 in aluminium intoxication is postreceptor in nature.
Merke
J
J
Department of Internal Medicine, University of Heidelberg, Federal Republic of Germany.
Lucas
P A
PA
Szabó
A
A
Helbing
F
F
Hügel
U
U
Drüeke
T
T
Ritz
E
E
D000535:Aluminum / Q000633:toxicity*; D000818:Animals; D001842:Bone and Bones / Q000378:metabolism; D002117:Calcitriol / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007700:Kinetics; D008297:Male; D010018:Osteomalacia / Q000209:etiology / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D018167:Receptors, Calcitriol; D011987:Receptors, Steroid / Q000378:metabolism*; D012708:Sertoli Cells / Q000378:metabolism; D012867:Skin / Q000378:metabolism; D014018:Tissue Distribution
D018167:Receptors, Calcitriol; D011987:Receptors, Steroid; D000535:Aluminum; D002117:Calcitriol; D002118:Calcium