Cyclosporin-A increases synthesis of 1,25-dihydroxyvitamin D3 in the rat and mouse.
We have previously observed elevated serum 1,25-dihydroxyvitamin D3 [1,25-(OH)2D] levels in male rats treated with oral cyclosporin-A (CsA). This elevation was independent of changes in PTH, ionized calcium, or phosphate. This paper investigates the potential sources and mechanisms for this increase in both rats and mice. Kidney homogenates from rats treated for 14 days with (15 mg/kg) had a significant increase in 25-hydroxyvitamin D (25OHD)-24-hydroxylase (24-hydroxylase) activity (149 +/- 20 vs. 89 +/- 16 fmol/mg.min; P less than 0.05), but nonsignificant increases in 25OHD-1 alpha-hydroxylase (1 alpha-hydroxylase) activity compared to controls. Kidney homogenates from C57b16J mice after the administration of 30-50 mg/kg CsA for 3 days revealed a linear dose-related increase in renal 1 alpha-hydroxylase (r = 0.96; P less than 0.05), which became significant with doses of 30 mg/kg CsA or more (P less than 0.05). To investigate the source of this 1,25-(OH)2D production, serum 1,25-(OH)2D was measured before and 48 h after bilateral nephrectomy in rats receiving CsA for 16 days. The percent decrease in serum 1,25-(OH)2D values was not significantly different in CsA-treated and untreated rats (33.9 +/- 4.9% vs. 47.5 +/- 4.9%), indicating little or no contribution from nonrenal sources. Studies of MCRs and production rates (PRs) revealed that the elevated 1,25-(OH)2D values were due to enhanced production and not altered clearance (PR, 12.4 +/- 1.2 vs. 19.1 +/- 1.9 fmol/mg.min; P less than 0.01). CsA increases 1 alpha-hydroxylase activity and produces significant elevations in serum 1,25-(OH)2D levels in both rats and mice. This increase may have an impact on bone mineral metabolism and immune modulation in postorgan transplantation patients.
Stein
B
B
Department of Medicine, Albert Einstein Medical Center, Temple University, Philadelphia, Pennsylvania 19141.
Halloran
B P
BP
Reinhardt
T
T
Engstrom
G W
GW
Bales
C W
CW
Drezner
M K
MK
Currie
K L
KL
Takizawa
M
M
Adams
J S
JS
Epstein
S
S
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000378:metabolism; D000818:Animals; D002117:Calcitriol / Q000096:biosynthesis* / Q000097:blood; D003524:Cyclosporins / Q000494:pharmacology*; D007668:Kidney / Q000201:enzymology; D008297:Male; D051379:Mice; D009392:Nephrectomy; D051381:Rats; D011919:Rats, Inbred Strains
D003524:Cyclosporins; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol