Effect of glyoxylate on the function of the calcitriol receptor and vitamin D metabolism.
The biological action of calcitriol is mostly mediated through the interaction of the calcitriol receptor (VDR) with vitamin D response elements (VDREs) of target genes. These interactions produce special proteins that carry out the biological activities of calcitriol. Recently, we showed that the interaction of VDRs with VDREs is inhibited by uremic toxins. We hypothesize that uremic toxins that contain aldehyde or ketone groups potentially could form Schiff bases with lysine residues of the VDR DNA binding domain and inhibit VDR interaction with VDREs. We therefore chose glyoxylate, a compound which has an aldehyde group, to test this hypothesis. In vitro glyoxylate inhibited VDR binding to the osteocalcin and osteopontin VDREs as assessed by electrophoretic mobility shift assay and the inhibition was reversed when glyoxylate was preincubated with lysine. Further, this chemical compound also blocked the induction of chloramphenicol acetyltransferase (CAT) enzyme induced by calcitriol in cells transfected with a calcitriol responsive CAT reporter gene. Since induction of 24-hydroxylase synthesis is a VDR regulated process, we also studied the effect of glyoxylate on the activity of intestinal 24-hydroxylase in rats. This enzyme activity was suppressed in rats infused with glyoxylate. Taken together, our study suggests that glyoxylate could inhibit the interaction of VDR with VDREs and alter the biological action of calcitriol.
Patel
S R
SR
Nephrology Division, University of Michigan Medical School, Ann Arbor, USA.
Xu
Y
Y
Koenig
R J
RJ
Hsu
C H
CH
D000818:Animals; D002117:Calcitriol / Q000494:pharmacology; D002478:Cells, Cultured; D002822:Choriocarcinoma / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System; D004305:Dose-Response Relationship, Drug; D017930:Genes, Reporter; D006038:Glyoxylates / Q000494:pharmacology*; D006801:Humans; D007422:Intestines / Q000201:enzymology; D015675:Osteocalcin / Q000235:genetics; D053495:Osteopontin; D051381:Rats; D018167:Receptors, Calcitriol / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D012795:Sialoglycoproteins / Q000235:genetics; D013250:Steroid Hydroxylases / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D014807:Vitamin D / Q000378:metabolism*; D065668:Vitamin D3 24-Hydroxylase
D006038:Glyoxylates; D018167:Receptors, Calcitriol; D011994:Recombinant Proteins; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; C506897:Spp1 protein, rat; D015675:Osteocalcin; D053495:Osteopontin; D014807:Vitamin D; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol; C031150:glyoxylic acid