The vitamin D analog, KH1060, is rapidly degraded both in vivo and in vitro via several pathways: Principal metabolites generated retain significant biological activity

Endocrinology

Volumn 138, Issue 12, 1997, Pages 5485-5496

  Dilworth, F Jeffrey ^a   Williams, Graham R ^b   Kissmeyer, Anne Marie ^c   Nielsen, Jeanet Løgsted ^c   Binderup, Ernst ^c   Calverley, Martin J ^c   Makin, Hugh L J ^d   Jones, Glenville ^a  

^a QUEEN S UNIVERSITY   (Canada)

^b HAMMERSMITH HOSPITAL   (United Kingdom)

^c LEO PHARMA A S   (Denmark)

^d UNIVERSITY OF LONDON   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

LEXACALCITOL;

ARTICLE; CANCER; CELL PROLIFERATION; DRUG METABOLISM; DRUG USE; GRAFT REJECTION; HUMAN; HUMAN CELL; HYPERCALCEMIA; PRIORITY JOURNAL; TARGET CELL;

EID: 0030698176     PISSN: 00137227     EISSN: None     Source Type: Journal    
DOI: 10.1210/endo.138.12.5594     Document Type: Article

References (47)

1. Bouillon R, Okamura WH, Norman AW 1995 Structure-function relationships in the vitamin D endocrine system. Endocr Rev 16:200-257
2. Jones G, Calverley, MJ 1993 A dialogue on analogues: newer vitamin-D drugs for use in bone disease, psoriasis, and cancer. Trends Endocrinol Metab 4:297-303
3. 2 suppresses PTH secretion in uremic rats in the absence of hypercalcemia. J Bone Miner Res 10:S167 (Abstract 116)
4. Gulliford T, English J, Colston K, Sprogel P, Coombes RC 1996 A phase 1 study of EB1089, a vitamin D analogue. Proc Am Assoc Cancer Res 37:164 (Abstract)
5. Hansen K, Calverley MJ, Binderup L 1991 Synthesis and biological activity of 22-oxa vitamin D analogues. In: Norman AVV, Bouillon R, Thomasset M (eds) Gene Regulation, Structure-Function Analysis and Clinical Applications. De Gruyter, Berlin, pp 161-162
6. 3 analogues: a novel class of potent regulators of cell growth and immune responses. Biochem Pharmacol 42:1569-1575
7. Ryhanen S, Mahonen A, Jaaskelainen T, Maenpaa PH 1996 Synthetic 20-epi analogs of calcitriol are potent inducers of target-gene activation in osteoblastic cells. Eur J Biochem 238:97-103
8. Wiberg K, Ljunghall S, Binderup L, Ljunggren O 1995 Studies on the two new-vitamin D analogs, EB1089 and KH1060: effects on bone resorption and osteoclast recruitment in vitro. Bone 17:391-395
9. 3 analogs on osteoblast-like cells and on in vitro bone resorption. J Steroid Biochem Mol Biol 55:337-346
10. 3 co-operate to promote differentiation of the human promyeloid leukemia cell line HL60 to monocytes. Leukemia 8:806-815
11. Branisteanu DD, Mathieu C, Casteels K, Bouillon R 1996 Combination of vitamin D analogues and immunosuppressants; potential clinical use. Clin Immunotherapeutics 6:465-478
12. Veyron P, Pamphile R, Binderup L, Touraine JL 1993 Two novel vitamin D analogues, KH 1060 and CB 966, prolong skin allograft survival in mice. Transplant Immunol 1:72-76
13. Kissmeyer A-M, Mathiasen IS, Latini S, Binderup L 1995 Pharmacokinetic studies of vitamin D analogues: relationship to vitamin D binding protein (DBP). Endocrine 3:263-266
14. Bouillon R, Allewaert K, Xiang DZ, Tan BK, Van Baelen H 1991 Vitamin D analogs with low affinity for the vitamin D binding protein: enhanced in vitro and decreased in vivo activity. J Bone Miner Res 6:1051-1057
15. 3 are associated with enhanced activation of the vitamin D receptor. J Biol Chem 270:10551-10558
16. 3 (VD) analogues MC903, EB1089, and KH1060 activate the VD receptor: homodimers show higher ligand sensitivity than heterodimers with retinoid X receptors. J Steroid Biochem Mol Biol 51:137-142
17. 3 analog, KH1060. Proc Natl Acad Sci USA 93:10685-10690
18. 3 in a keratinocyte model of tumor progression. J Biol Chem 267:12162-12167
19. Martin TJ, Ingleton PM, Underwood JCE, Michelangeli VP, Hunt NH, Melick RA 1976 Parathyroid hormone-responsive adenylate cyclase in induced transplantable osteogenic rat sarcoma. Nature 260:436-438
20. Aden DP, Fogel A, Plotkin S, Damjanov I, Knowles BB 1979 Controlled synthesis of HBsAg in a differentiated human liver carcinoma-derived cell line. Nature 282:615-616
21. Fogh J, Wright WC, Loveless JD 1977 Absence of HeLa cell contamination in 169 cell lines derived from human tumours. J Natl Cancer Inst 58:209-214
22. Majeska RJ, Rodan SB, Rodan GA 1980 Parathyroid hormone-responsive clonal cell lines from rat osteosarcoma. Endocrinology 107:1494-1503
23. Yoon K, Buenaga R, Rodan GA 1987 Tissue specificity and developmental expression of rat osteopontin. Biochem Biophys Res Commun 148:1129-1136
24. 3 24-hydroxylase cDNA Proc Natl Acad Sci USA 90:4543-4547
25. Chan Y, Gutell R, Noller HF, Wool IG 1984 The nucleotide sequence of a rat 18S ribosomal ribonucleic acid gene and a proposal for the secondary structure of 18S ribosomal ribonucleic acid. J Biol Chem 259:224-230
26. 3 analogue. Bioorg Med Chem Lett 2:1713-1716
27. 3 is due to reduced catabolism and altered protein binding. Biochem Pharmacol 47:987-993
28. 3 in a hepatocyte cell model. Biochem Pharmacol 40:333-341
29. Hollis BW 1986 Assay of circulating 1,25-dihydroxyvitamin D involving a novel single cartridge extraction and purification procedure. Clin Chem 32:2060-2063
30. 3 analogs potently induce the human osteocalcin gene promoter stably transfected into rat osteosarcoma cells (ROSCO-2). J Bone Miner Res 6:893-899
31. Sleigh MJ 1986 A nonchromatographic assay for expression of the chloramphenicol acetyltransferase gene in eucaryotic cells. Anal Biochem 156:251-256
32. Chomczynski P, Sacchi N 1987 Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162:156-159
33. 3, and retinoid signalling. Endocrinology 135:2375-2385
34. 3 are differentially modified by 9-cis retinoic acid. Cancer Res 56:623-632
35. Masuda S, Byford V, Kremer R, Makin HLJ, Kubodera N, Nishii Y, Okazaki A, Okano T, Kobayashi T, Jones G 1996 In vitro metabolism of the vitamin D analog, 22-oxacalcitriol, using cultured osteosarcoma, hepatoma, and keratinocyte cell lines. J Biol Chem 271:8700-8708
36. 3 to calcitroic acid. Evidence for a pathway in kidney and bone involving 24-oxidation. Biochem J 262:173-180
37. 2 m normal and immortalized human epidermal cells. Biochem Pharmacol 52:133-140
38. Shankar VN, Dilworth FJ, Makin HLJ, Schroeder NJ, Trafford DAJ, Kissmeyer A-M, Calverley MJ, Binderup E, Jones G 1997 Metabolism of the vitamin D analog EB1089 by cultured human cells: redirection of hydroxylation site to distal carbons of the side-chain. Biochem Pharmacol 53:783-793
39. Kissmeyer A-M, Binderup E, Binderup L, Hansen CM, Andersen NR, Schroeder NJ, Makin HLJ, Shankar VN, Jones G 1997 The metabolism of the vitamin D analog EB 1089: identification of in vivo and in vitro metabolites and their biological activities. Biochem Pharmacol 53:1087-1097
40. Dilworth FJ, Scott I, Green A, Strugnell S, Guo Y-D, Roberts EA, Kremer R, Calverley MJ, Makin HLJ, Jones G 1995 Different mechanisms of hydroxylation site selection by liver and kidney cytochrome P450 species (CYP27 and CYP24) involved in vitamin D metabolism. J Biol Chem 270:16766-16774
41. Akiyoshi-Shibata M, Sakaki T, Ohyama Y, Noshiro M, Okuda K, Yabusaki Y 1994 Further oxidation of hydroxycalcidiol by calcidiol 24-hydroxylase - a study with the mature enzyme expressed in Escherichia coli. Eur J Biochem 224:335-343
42. 3-26,23-lactone biosynthesis. Biochemistry 23:3973-3976
43. 3 in target cells. Proceedings of the First International Congress on Vitamins and Biofactors in Life Science. J Nutr Sci Vitaminol (Special Issue), pp 75-78
44. 3. J Biol Chem 272:14115-14119
45. 3-24-hydroxylase activity in Caco-2 cells: an in vitro model of intestinal vitamin D catabolism. Endocrinology 126:2868-2875
46. Jones G 1996 Pharmacological mechanisms of therapeutics: vitamin D and analogs. In: Raisz L, Rodan G, Bilezikian J (eds) Principles of Bone Biology, sect 3, chapt 77. Academic Press, San Diego, pp 1069-1082
47. Dilworth FJ, Calverley MJ, Kissmeyer A-M, Binderup E, Makin HLJ, Jones G 1996 KH1060. A potent vitamin D analog is degraded in cultured keratinocytes via several different pathways. J Bone Miner Res 11:S424 (Abstract T500)