D-vitamin är ett fettlösligt vitamin som antingen kan intas från födan bl.a. fet fisk eller äggula eller bildas i huden då den bestrålas av solljus. Vitamin D indelas i två typer, vitamin D2 (växter) och vitamin D3 (djur, människor).
Vitamin D3 i sig har inte någon effekt, utan måste aktiveras i kroppen i två
steg. Första aktiveringssteget sker i levern och bildar kalcidiol (25- hydroxyvitamin D3), sedan sker andra aktiveringssteget i njuren och bildar
det aktiva vitamin D-hormonet kalcitriol (1,25-hydroxyvitamin D3). Aktivt
vitamin D3 har många viktiga effekter; bland de viktigaste är effekten på
benhälsan genom att underlätta kalciumabsorptionen från tarmarna och normal benbildning. Vitamin D3 är avgörande för upprätthållandet av
normala kalciumnivåer, vilket är viktigt även för att musklerna ska kunna arbeta på rätt sätt. Studier har funnit att brist på vitamin D3 ökar risken för
störningar av många av kroppens fysiologiska processer såsom hormonbalans och immunförsvaret. Samband har påvisats mellan vitamin D- brist och skelettsjukdomar, såsom rakit och benskörhet, olika cancerformer och immunsjukdomar. Ytterligare studier har visat samband mellan vitamin D3 och hjärnan, där brist under utvecklingen kan vara en riskfaktor för flera
neurodegenerativa störningar och utveckling av hjärnsjukdomar t.ex. schizofreni, autism och Parkinsons sjukdom.
Steroidhormoner, liksom D-vitamin, härrör från kolesterol och kan delas in i tre grupper, glukokortikoider (t.ex. kortisol), mineralokortikoider (t.ex. aldosteron) och könshormoner (t.ex. testosteron och östradiol). Androgener och östrogener spelar en viktig roll vid reproduktion och utveckling av sekundära könskarakteristika hos män respektive kvinnor. Den aktiva formen av vitamin D3, 1,25-dihydroxyvitamin D3, karakteriseras som ett
steroidhormon eftersom den använder en receptor-medierad interaktion med målgenerna. CYP450 är en familj av enzymer, som är proteiner vars funktion är såsom biologiska katalysatorer i kroppen, vilka påskyndar kemiska reaktioner som är inblandade i bildning och nedbrytning av läkemedel och kroppsegna ämnen. CYP450-enzymer är involverade i många fysiologiska reaktioner såsom aktivering och inaktivering av vitamin D, gallsyrabiosyntes och steroidsyntes. Kolesterol är en viktig källa för bildning av bl.a. steroidhormoner och vitamin D och finns rikligt i hjärnan. Kolesterol
är avgörande för många processer i kroppen. Trots att levern är huvudorganet för att syntetisera kolesterol, har många andra kroppsvävnader också denna förmåga.
I denna avhandling undersöktes om NSC-34 celler kunde representera en modell för hjärnceller och användas i studier av neuronal vitamin D- metabolism och reglering av aktiva D-vitaminhalter i CNS. Resultaten visade att dessa celler uttrycker mRNA för enzymerna, som är inblandade i vitamin D aktivering och inaktivering samt för vitamin D-receptorn (VDR). Det visade sig att dessa celler även bildar den CYP24A1-producerade metaboliten 24,25-dihydroxyvitamin D3. CYP24A1 är ett enzym vars
funktion är att inaktivera det aktiva vitamin D3-hormonet. Dessutom tyder
resultaten på metabolism och reglering av flera vitamin D3-föreningar i
dessa celler. mRNA-nivåerna för CYP24A1 uppreglerades vid behandling med 1,25-hydroxivitamin D3 och vitamin D-analogerna EB1089 och
tacalcitol (syntetiska ämnen med strukturella likheter med vitamin D). Resultaten tyder på att NSC-34-celler kan vara en ny modell för studier av neuronal vitamin D-metabolism och dess reglering av endogena och exogena föreningar. Resultat från experiment med NSC-34 celler och primära neuronrika celler från rått-hjärncortex visade en signifikant tidsberoende minskning av 25-hydroxyvitamin D3 halter vid inkubering. Experiment med
radioaktivt 25-hydroxyvitamin D3 kunde påvisa en ny tidigare okänd
metabolit som kan vara orsaken till substratminskningen. Läkemedlet prednisolon visade en hämmande effekt på substratminskningen i båda celltyperna men ökat mRNA uttryck av CYP24A1 i NSC-34 celler. Effekterna av glukokortikoider på vitamin D-metabolismen i humana benceller studerades också. Bencellerna visade uttryck av mRNA för alla enzymer som krävs i vitamin D3-metabolismen. Dessutom kan de producera
metaboliten 24,25-dihydroxyvitamin D3 från 25-hydroxyvitamin D3.
Behandling med glukokortikoider (till exempel kortisol och prednisolon) visade en nedreglerande effekt på mRNA-uttrycket för CYP24A1-genen i bencellerna. Utöver detta påvisades bildning av glukokortikoiden 11- deoxykortisol. I avhandlingen studerades dessutom uttrycket av CYP17A1 och 3β-HSD i humana neuroblastom-celler, primära rått-astrocyter och primära neuronrika celler från rått-hjärncortex från nervsystemet. Effekter av vitamin D3 på dessa enzymer undersöktes. Resultaten tyder på att vitamin D-
medierad reglering av CYP17A1 och 3β-HSD, speciellt på mRNA-nivå, kan spela en viktig roll i nervsystemet. Sammanfattningsvis kan resultaten i denna avhandling bidra till bättre förståelse av vitamin D-metabolismen och effekterna av glukokortikoider i hjärnan och skelettet.
Acknowledgement
The work presented in this species was carried out at the Department of Pharmaceutical Biosciences, Faculty of Pharmacy, Uppsala University, Sweden.
This work was financially supported by the Swedish Research Council Medicine.
I would like to express my sincere gratitude to:
My supervisors, Associate professor Maria Norlin and Professor Kjell Wikvall, for all the invaluable help I have received in all fields during my time as your PhD student. Also, a big thank you for your contagious enthusiasm for science and always keeping the door to your office open. One could not hope for better supervisors.
Ahmad Z, and Ida E, my colleagues and co-authors, for good times and nice company both home and abroad as well as for your valuable co-operation. To my present and former colleagues in Uppsala, Thank you for your positivity, kindness and support. Björn H, Lisa F-C, Tomas F, Emelie K, Ronnie H, Kerstin R, Hanna P, Christine W, Per A, Anna N, Patrik K, Henrik W, Reza S, Theodosia V, Elva F, Alfhild G, Erika B, Anna J, Erik N, Mattias H, Kumari U, Anna L, Marina R, Inga H, Georgy B, Tatiana I, Igor B, Wei S, Magnus E, Anne-lie S, Lisa E, Ernst O, Eva B, Lena N, Åsa F-S. To my dear friends, Ahmad A, Loai H, Ali A, Rawand N, Ghaith M, Isam A, Nasim A, Mohammed M, Hashim O, Karar K, Musthaq A, Muntadhar A, Bashar A, Mustafa A. Ali H, Maher M. A, Laith A. Thank you for useful advice and our fun times together and for all my other friends, for their good friendship.
Finally, to all my family and parents, thank you for your endless love and support.
References
Alberti, S., Schuster, G., Parini, P., Feltkamp, D., Diczfalusy, U., Rudling, M., Angelin, B., Björkhem, I., Pettersson, S., Gustafsson, J.-Å., 2001. Hepatic cholesterol metabolism and resistance to dietary cholesterol in LXRβ-deficient mice. J. Clin. Invest. 107, 565–573.
Almokhtar, M., Wikvall, K., Ubhayasekera, S.J.K.A., Bergquist, J., Norlin, M., 2016. Motor neuron-like NSC-34 cells as a new model for the study of vitamin D metabolism in the brain. J. Steroid Biochem. Mol. Biol. 158, 178–188. https://doi.org/10.1016/j.jsbmb.2015.12.010
Annweiler, C., Schott, A.-M., Berrut, G., Chauviré, V., Le Gall, D., Inzitari, M., Beauchet, O., 2010. Vitamin D and ageing: neurological issues. Neuropsychobiology 62, 139–150. https://doi.org/10.1159/000318570
Araya, Z., Tang, W., Wikvall, K., 2003. Hormonal regulation of the human sterol 27-hydroxylase gene CYP27A1. Biochem. J. 372, 529–534. https://doi.org/10.1042/bj20021651
Arnold, J.T., Le, H., McFann, K.K., Blackman, M.R., 2005. Comparative effects of DHEA vs. testosterone, dihydrotestosterone, and estradiol on proliferation and gene expression in human LNCaP prostate cancer cells. Am. J. Physiol. Endocrinol. Metab. 288, E573–584. https://doi.org/10.1152/ajpendo.00454.2004 Atkins, G.J., Anderson, P.H., Findlay, D.M., Welldon, K.J., Vincent, C., Zannettino, A.C.W., O’Loughlin, P.D., Morris, H.A., 2007. Metabolism of vitamin D3 in
human osteoblasts: evidence for autocrine and paracrine activities of 1 alpha,25- dihydroxyvitamin D3. Bone 40, 1517–1528.
https://doi.org/10.1016/j.bone.2007.02.024
Baulieu, E.E., 1998. NEUROSTEROIDS: A NOVEL FUNCTION OF THE BRAIN. Psychoneuroendocrinology 23, 963–987. https://doi.org/10.1016/S0306-4530(98)00071-7
Baulieu, E.E., 1997. Neurosteroids: of the nervous system, by the nervous system, for the nervous system. Recent Prog. Horm. Res. 52, 1–32.
Björkhem, I., Cedazo-Minguez, A., Leoni, V., Meaney, S., 2009. Oxysterols and neurodegenerative diseases. Mol. Aspects Med. 30, 171–179. https://doi.org/10.1016/j.mam.2009.02.001
Björkhem, I., Hansson, M., 2010. Cerebrotendinous xanthomatosis: An inborn error in bile acid synthesis with defined mutations but still a challenge. Biochem. Biophys. Res. Commun., Recent Progress in Molecular Sciences: Reviews from Karolinska Institutet at its 200-year Anniversary 396, 46–49. https://doi.org/10.1016/j.bbrc.2010.02.140
Björkhem, I., Meaney, S., Diczfalusy, U., 2002. Oxysterols in human circulation: which role do they have? Curr. Opin. Lipidol. 13, 247–253.
Blondon, M., Sachs, M., Hoofnagle, A.N., Ix, J.H., Michos, E.D., Korcarz, C., Gepner, A.D., Siscovick, D.S., Kaufman, J.D., Stein, J.H., Kestenbaum, B., de Boer, I.H., 2013. 25-Hydroxyvitamin D and parathyroid hormone are not associated with carotid intima-media thickness or plaque in the multi-ethnic study of atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 33, 2639–2645.
Brinkmann, A.O., Blok, L.J., de Ruiter, P.E., Doesburg, P., Steketee, K., Berrevoets, C.A., Trapman, J., 1999. Mechanisms of androgen receptor activation and function. J. Steroid Biochem. Mol. Biol. 69, 307–313. https://doi.org/10.1016/S0960-0760(99)00049-7
Bruzzone, F., Do Rego, J.-L., Luu-The, V., Pelletier, G., Vallarino, M., Vaudry, H., 2010. Immunohistochemical localization and biological activity of 3beta- hydroxysteroid dehydrogenase and 5alpha-reductase in the brain of the frog, Rana esculenta, during development. J. Chem. Neuroanat. 39, 35–50. https://doi.org/10.1016/j.jchemneu.2009.08.001
Caetano-Lopes, J., Canhão, H., Fonseca, J.E., 2007. Osteoblasts and bone formation. Acta Reumatol. Port. 32, 103–110.
Cahill, L., McGaugh, J.L., 1998. Mechanisms of emotional arousal and lasting declarative memory. Trends Neurosci. 21, 294–299.
Cali, J.J., Hsieh, C.L., Francke, U., Russell, D.W., 1991. Mutations in the bile acid biosynthetic enzyme sterol 27-hydroxylase underlie cerebrotendinous xanthomatosis. J. Biol. Chem. 266, 7779–7783.
Cascio, C., Brown, R.C., Liu, Y., Han, Z., Hales, D.B., Papadopoulos, V., 2000. Pathways of dehydroepiandrosterone formation in rat brain glia. J. Steroid Biochem. Mol. Biol. 75, 177–186.
Cashman, N.R., Durham, H.D., Blusztajn, J.K., Oda, K., Tabira, T., Shaw, I.T., Dahrouge, S., Antel, J.P., 1992. Neuroblastoma x spinal cord (NSC) hybrid cell lines resemble developing motor neurons. Dev. Dyn. Off. Publ. Am. Assoc. Anat. 194, 209–221. https://doi.org/10.1002/aja.1001940306
Cederbaum, A.I., 2015. Molecular mechanisms of the microsomal mixed function oxidases and biological and pathological implications. Redox Biol. 4, 60–73. Chang, G.W.M., Kam, P.C.A., 1999. The physiological and pharmacological roles
of cytochrome P450 isoenzymes. Anaesthesia 54, 42–50. https://doi.org/10.1046/j.1365-2044.1999.00602.x
Chee, C., Sellahewa, L., Pappachan, J.M., 2014. Inhaled Corticosteroids and Bone Health. Open Respir. Med. J. 8, 85–92. https://doi.org/10.2174/1874306401408010085
Cheng, J.B., Motola, D.L., Mangelsdorf, D.J., Russell, D.W., 2003. De-orphanization of cytochrome P450 2R1: a microsomal vitamin D 25-hydroxilase. J. Biol. Chem. 278, 38084–38093. https://doi.org/10.1074/jbc.M307028200
Cheskis, B.J., Greger, J.G., Nagpal, S., Freedman, L.P., 2007. Signaling by estrogens. J. Cell. Physiol. 213, 610–617. https://doi.org/10.1002/jcp.21253 Chiellini, G., Rapposelli, S., Zhu, J., Massarelli, I., Saraceno, M., Bianucci, A.M.,
Plum, L.A., Clagett-Dame, M., DeLuca, H.F., 2012. Synthesis and biological activities of vitamin D-like inhibitors of CYP24 hydroxylase. Steroids 77, 212– 223. https://doi.org/10.1016/j.steroids.2011.11.007
Christakos, S., Dhawan, P., Liu, Y., Peng, X., Porta, A., 2003. New insights into the mechanisms of vitamin D action. J. Cell. Biochem. 88, 695–705. https://doi.org/10.1002/jcb.10423
Coldwell, R.D., Porteous, C.E., Trafford, D.J.H., Makin, H.L.J., 1987. Gas chromatography—mass spectrometry and the measurement of vitamin D metabolites in human serum or plasma. Steroids 49, 155–196. https://doi.org/10.1016/0039-128X(87)90083-3
Compagnone, N.A., Zhang, P., Vigne, J.-L., Mellon, S.H., 2000. Novel Role for the Nuclear Phosphoprotein SET in Transcriptional Activation of P450c17 and Initiation of Neurosteroidogenesis. Mol. Endocrinol. 14, 875–888. https://doi.org/10.1210/mend.14.6.0469
Cozzolino, M., Vidal, M., Arcidiacono, M.V., Tebas, P., Yarasheski, K.E., Dusso, A.S., 2003. HIV-protease inhibitors impair vitamin D bioactivation to 1,25- dihydroxyvitamin D. AIDS Lond. Engl. 17, 513–520. https://doi.org/10.1097/01.aids.0000050817.06065.f8
Davidson, Z.E., Walker, K.Z., Truby, H., 2012. Clinical review: Do glucocorticosteroids alter vitamin D status? A systematic review with meta- analyses of observational studies. J. Clin. Endocrinol. Metab. 97, 738–744. https://doi.org/10.1210/jc.2011-2757
Degtyarenko, K.N., Archakov, A.I., 1993. Molecular evolution of P450 superfamily and P450-containing monooxygenase systems. FEBS Lett. 332, 1–8. https://doi.org/10.1016/0014-5793(93)80470-F
DeLuca, G.C., Kimball, S.M., Kolasinski, J., Ramagopalan, S.V., Ebers, G.C., 2013. Review: The role of vitamin D in nervous system health and disease. Neuropathol. Appl. Neurobiol. 39, 458–484. https://doi.org/10.1111/nan.12020 DeLuca, H.F., 1981. Recent Advances in the Metabolism of Vitamin D. Annu. Rev.
Physiol. 43, 199–209. https://doi.org/10.1146/annurev.ph.43.030181.001215 DeLuca, H.F., Schnoes, H.K., 1983. Vitamin D: recent advances. Annu. Rev.
Biochem. 52, 411–439. https://doi.org/10.1146/annurev.bi.52.070183.002211 Dhawan, P., Christakos, S., 2010. Novel regulation of 25-hydroxyvitamin D3 24-
hydroxylase (24(OH)ase) transcription by glucocorticoids: cooperative effects of the glucocorticoid receptor, C/EBP beta, and the Vitamin D receptor in 24(OH)ase transcription. J. Cell. Biochem. 110, 1314–1323. https://doi.org/10.1002/jcb.22645
Diwakarla, S., Nylander, E., Grönbladh, A., Vanga, S.R., Khan, Y.S., Gutiérrez-de- Terán, H., Ng, L., Pham, V., Sävmarker, J., Lundbäck, T., Jenmalm-Jensen, A., Andersson, H., Engen, K., Rosenström, U., Larhed, M., Åqvist, J., Chai, S.Y., Hallberg, M., 2016. Binding to and Inhibition of Insulin-Regulated Aminopeptidase by Macrocyclic Disulfides Enhances Spine Density. Mol. Pharmacol. 89, 413–424. https://doi.org/10.1124/mol.115.102533
Do Rego, J.L., Seong, J.Y., Burel, D., Leprince, J., Luu-The, V., Tsutsui, K., Tonon, M.-C., Pelletier, G., Vaudry, H., 2009. Neurosteroid biosynthesis: Enzymatic pathways and neuroendocrine regulation by neurotransmitters and neuropeptides. Front. Neuroendocrinol. 30, 259–301. https://doi.org/10.1016/j.yfrne.2009.05.006
Do Rego, J.L., Tremblay, Y., Luu-The, V., Repetto, E., Castel, H., Vallarino, M., Bélanger, A., Pelletier, G., Vaudry, H., 2007. Immunohistochemical localization and biological activity of the steroidogenic enzyme cytochrome P450 17alpha- hydroxylase/C17, 20-lyase (P450C17) in the frog brain and pituitary. J. Neurochem. 100, 251–268. https://doi.org/10.1111/j.1471-4159.2006.04209.x Drezner, M.K., Lyles, K.W., Haussler, M.R., Harrelson, J.M., 1980. Evaluation of a
role for 1,25-dihydroxyvitamin D3 in the pathogenesis and treatment of X-
linked hypophosphatemic rickets and osteomalacia. J. Clin. Invest. 66, 1020– 1032. https://doi.org/10.1172/JCI109930
Dursun, E., Gezen-Ak, D., Yilmazer, S., 2013a. Beta amyloid suppresses the expression of the vitamin d receptor gene and induces the expression of the vitamin d catabolic enzyme gene in hippocampal neurons. Dement. Geriatr. Cogn. Disord. 36, 76–86. https://doi.org/10.1159/000350319
Dursun, E., Gezen-Ak, D., Yilmazer, S., 2013b. Beta amyloid suppresses the expression of the vitamin d receptor gene and induces the expression of the vitamin d catabolic enzyme gene in hippocampal neurons. Dement. Geriatr. Cogn. Disord. 36, 76–86. https://doi.org/10.1159/000350319
Dusso, A.S., Brown, A.J., Slatopolsky, E., 2005. Vitamin D. Am. J. Physiol. Renal Physiol. 289, F8–28. https://doi.org/10.1152/ajprenal.00336.2004
Edinger, K.L., Frye, C.A., 2007. Androgens’ effects to enhance learning may be mediated in part through actions at estrogen receptor-β in the hippocampus. Neurobiol. Learn. Mem. 87, 78–85. https://doi.org/10.1016/j.nlm.2006.07.001 Ellfolk, M., Norlin, M., Wikvall, K., 2006. Isolation and properties of the CYP2D25
promoter: transcriptional regulation by vitamin D3 metabolites. Biochem. Biophys.
Res. Commun. 345, 568–572. https://doi.org/10.1016/j.bbrc.2006.04.116
Eyles, D.W., Burne, T.H.J., McGrath, J.J., 2013. Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front. Neuroendocrinol. 34, 47–64. https://doi.org/10.1016/j.yfrne.2012.07.001
Féron, F., Burne, T.H.J., Brown, J., Smith, E., McGrath, J.J., Mackay-Sim, A., Eyles, D.W., 2005. Developmental Vitamin D3 deficiency alters the adult rat brain. Brain
Res. Bull. 65, 141–148. https://doi.org/10.1016/j.brainresbull.2004.12.007
Fex Svenningsen, A., Wicher, G., Lundqvist, J., Pettersson, H., Corell, M., Norlin, M., 2011. Effects on DHEA levels by estrogen in rat astrocytes and CNS co- cultures via the regulation of CYP7B1-mediated metabolism. Neurochem. Int. 58, 620–624. https://doi.org/10.1016/j.neuint.2011.01.024
Frye, C.A., Van Keuren, K.R., Erskine, M.S., 1996. Behavioral effects of 3α- androstanediol I: modulation of sexual receptivity and promotion of GABA- stimulated chloride flux. Behav. Brain Res. 79, 109–118. https://doi.org/10.1016/0166-4328(96)00004-6
Fu, G.K., Lin, D., Zhang, M.Y., Bikle, D.D., Shackleton, C.H., Miller, W.L., Portale, A.A., 1997. Cloning of human 25-hydroxyvitamin D-1 alpha-hydroxylase and mutations causing vitamin D-dependent rickets type 1. Mol. Endocrinol. Baltim. Md 11, 1961–1970. https://doi.org/10.1210/mend.11.13.0035
Garfinkel, D., 1958. Studies on pig liver microsomes. I. Enzymic and pigment composition of different microsomal fractions. Arch. Biochem. Biophys. 77, 493–509. https://doi.org/10.1016/0003-9861(58)90095-X
Gottschling, C., Dzyubenko, E., Geissler, M., Faissner, A., 2016. The Indirect Neuron-astrocyte Coculture Assay: An In Vitro Set-up for the Detailed Investigation of Neuron-glia Interactions. J. Vis. Exp. JoVE. https://doi.org/10.3791/54757
Harms, L.R., Burne, T.H.J., Eyles, D.W., McGrath, J.J., 2011. Vitamin D and the brain. Best Pract. Res. Clin. Endocrinol. Metab. 25, 657–669. https://doi.org/10.1016/j.beem.2011.05.009
Haussler, M.R., Haussler, C.A., Jurutka, P.W., Thompson, P.D., Hsieh, J.C., Remus, L.S., Selznick, S.H., Whitfield, G.K., 1997. The vitamin D hormone and its nuclear receptor: molecular actions and disease states. J. Endocrinol. 154 Suppl, S57–73. Henry, H.L., 2011. Regulation of vitamin D metabolism. Best Pract. Res. Clin.
Endocrinol. Metab. 25, 531–541. https://doi.org/10.1016/j.beem.2011.05.003 Hess, R.A., Bunick, D., Lee, K.-H., Bahr, J., Taylor, J.A., Korach, K.S., Lubahn,
D.B., 1997. A role for oestrogens in the male reproductive system. Nature 390, 509–12. https://doi.org/10.1038/37352
Hojo, Y., Hattori, T.-A., Enami, T., Furukawa, A., Suzuki, K., Ishii, H.-T., Mukai, H., Morrison, J.H., Janssen, W.G.M., Kominami, S., Harada, N., Kimoto, T., Kawato, S., 2004. Adult male rat hippocampus synthesizes estradiol from pregnenolone by cytochromes P45017alpha and P450 aromatase localized in neurons. Proc. Natl. Acad. Sci. U. S. A. 101, 865–870. https://doi.org/10.1073/pnas.2630225100
Holick, M.F., 2008. The Vitamin D Deficiency Pandemic and Consequences for Nonskeletal Health: Mechanisms of Action. Mol. Aspects Med. 29, 361–368. https://doi.org/10.1016/j.mam.2008.08.008
Holick, M.F., 2005. Stay tuned to PXR: an orphan actor that may not be D-structive only to bone. J. Clin. Invest. 115, 32–34. https://doi.org/10.1172/JCI200523995 Holick, M.F., 1996. Vitamin D and bone health. J. Nutr. 126, 1159S–64S.
Holick, P. discussant: M.F., 1987. Vitamin D and the kidney. Kidney Int. 32, 912– 929. https://doi.org/10.1038/ki.1987.295
Ilias, I., Ghayee, H., 2000. Glucocorticoid-Induced Osteoporosis, in: De Groot, L.J., Chrousos, G., Dungan, K., Feingold, K.R., Grossman, A., Hershman, J.M., Koch, C., Korbonits, M., McLachlan, R., New, M., Purnell, J., Rebar, R., Singer, F., Vinik, A. (Eds.), Endotext. MDText.com, Inc., South Dartmouth (MA).
Jang, H., Choi, Y., Yoo, I., Han, J., Hong, J.S., Kim, Y.Y., Ka, H., 2017. Vitamin D-metabolic enzymes and related molecules: Expression at the maternal- conceptus interface and the role of vitamin D in endometrial gene expression in pigs. PloS One 12, e0187221. https://doi.org/10.1371/journal.pone.0187221 Janowski, B.A., Willy, P.J., Devi, T.R., Falck, J.R., Mangelsdorf, D.J., 1996. An
oxysterol signalling pathway mediated by the nuclear receptor LXRα. Nature 383, 383728a0. https://doi.org/10.1038/383728a0
Jiao, H., Olin, M., Hansson, M., Eggertsen, G., Eriksson, M., Angelin, B., Björkhem, I., 2017. Unique case of cerebrotendinous xanthomatosis revisited. All the mutations responsible for this disease are present in the CYP27A1 gene. J. Intern. Med. https://doi.org/10.1111/joim.12709
Jones, G., Prosser, D.E., Kaufmann, M., 2012. 25-Hydroxyvitamin D-24- hydroxylase (CYP24A1): its important role in the degradation of vitamin D. Arch. Biochem. Biophys. 523, 9–18. https://doi.org/10.1016/j.abb.2011.11.003 Katsu, Y., Kohno, S., Oka, K., Baker, M.E., 2016. Evolution of corticosteroid
specificity for human, chicken, alligator and frog glucocorticoid receptors. Steroids 113, 38–45. https://doi.org/10.1016/j.steroids.2016.06.005
Kindlundh-Högberg, A.M.S., Pickering, C., Wicher, G., Hobér, D., Schiöth, H.B., Fex Svenningsen, A., 2010. MDMA (Ecstasy) decreases the number of neurons and stem cells in embryonic cortical cultures. Cell. Mol. Neurobiol. 30, 13–21. https://doi.org/10.1007/s10571-009-9426-y
Klingenberg, M., 1958. Pigments of rat liver microsomes. Arch. Biochem. Biophys. 75, 376–386. https://doi.org/10.1016/0003-9861(58)90436-3
Kochupillai, N., 2008. The physiology of vitamin D : current concepts. Indian J. Med. Res. 127, 256–262.
Kolars, J.C., Lown, K.S., Schmiedlin-Ren, P., Ghosh, M., Fang, C., Wrighton, S.A., Merion, R.M., Watkins, P.B., 1994. CYP3A gene expression in human gut epithelium. Pharmacogenetics 4, 247–259.
Kuiper, G.G.J.M., Carlsson, B., Grandien, K., Enmark, E., Häggblad, J., Nilsson, S., Gustafsson, J.-Å., 1997. Comparison of the Ligand Binding Specificity and Transcript Tissue Distribution of Estrogen Receptors α and β. Endocrinology 138, 863–870. https://doi.org/10.1210/endo.138.3.4979
Kumar, R., Iachini, D.N., Neilsen, P.M., Kaplan, J., Michalakas, J., Anderson, P.H., May, B.K., Morris, H.A., Callen, D.F., 2010. Systematic characterisation of the rat and human CYP24A1 promoter. Mol. Cell. Endocrinol. 325, 46–53. https://doi.org/10.1016/j.mce.2010.04.023
Kurahashi, I., Matsunuma, A., Kawane, T., Abe, M., Horiuchi, N., 2002. Dexamethasone enhances vitamin D-24-hydroxylase expression in osteoblastic (UMR-106) and renal (LLC-PK1) cells treated with 1alpha,25-dihydroxyvitamin D3. Endocrine 17, 109–118. https://doi.org/10.1385/ENDO:17:2:109
Labrie, F., Luu-The, V., Labrie, C., Simard, J., 2001. DHEA and Its Transformation into Androgens and Estrogens in Peripheral Target Tissues: Intracrinology. Front. Neuroendocrinol. 22, 185–212. https://doi.org/10.1006/frne.2001.0216 Laffitte, B.A., Joseph, S.B., Walczak, R., Pei, L., Wilpitz, D.C., Collins, J.L.,
Tontonoz, P., 2001. Autoregulation of the Human Liver X Receptor α Promoter. Mol. Cell. Biol. 21, 7558–7568. https://doi.org/10.1128/MCB.21.22.7558- 7568.2001
Lehmann, J.M., Kliewer, S.A., Moore, L.B., Smith-Oliver, T.A., Oliver, B.B., Su, J.-L., Sundseth, S.S., Winegar, D.A., Blanchard, D.E., Spencer, T.A., Willson, T.M., 1997. Activation of the Nuclear Receptor LXR by Oxysterols Defines a New Hormone Response Pathway. J. Biol. Chem. 272, 3137–3140. https://doi.org/10.1074/jbc.272.6.3137
Leihy, M.W., Shaw, G., Wilson, J.D., Renfree, M.B., 2001. Virilization of the urogenital sinus of the tammar wallaby is not unique to 5α-androstane-3α,17β- diol. Mol. Cell. Endocrinol. 181, 111–115. https://doi.org/10.1016/S0303- 7207(01)00527-5
Luchetti, S., van Eden, C.G., Schuurman, K., van Strien, M.E., Swaab, D.F., Huitinga, I., 2014. Gender differences in multiple sclerosis: induction of estrogen signaling in male and progesterone signaling in female lesions. J. Neuropathol. Exp. Neurol. 73, 123–135. https://doi.org/10.1097/NEN.0000000000000037
Lundqvist, J., Norlin, M., Wikvall, K., 2011. 1α,25-Dihydroxyvitamin D3 exerts
tissue-specific effects on estrogen and androgen metabolism. Biochim. Biophys. Acta BBA - Mol. Cell Biol. Lipids 1811, 263–270. https://doi.org/10.1016/j.bbalip.2011.01.004
Lundqvist, J., Norlin, M., Wikvall, K., 2010. 1α,25-Dihydroxyvitamin D3 affects
hormone production and expression of steroidogenic enzymes in human adrenocortical NCI-H295R cells. Biochim. Biophys. Acta BBA - Mol. Cell Biol. Lipids 1801, 1056–1062. https://doi.org/10.1016/j.bbalip.2010.04.009 Luu-The, V., Bélanger, A., Labrie, F., 2008. Androgen biosynthetic pathways in the
human prostate. Best Pract. Res. Clin. Endocrinol. Metab., Endocrinology and the Prostate 22, 207–221. https://doi.org/10.1016/j.beem.2008.01.008
Manca, P., Caria, M.A., Blasi, J., Martín-Satué, M., Mameli, O., 2012. Cytochrome P450 17α-hydroxylase/C(17,20)-lyase immunoreactivity and molecular expression in the cerebellar nuclei of adult male rats. J. Chem. Neuroanat. 45, 18–25. https://doi.org/10.1016/j.jchemneu.2012.07.002
Mast, N., Anderson, K.W., Johnson, K.M., Phan, T.T.N., Guengerich, F.P., Pikuleva, I.A., 2017. In vitro cytochrome P450 46A1 (CYP46A1) activation by neuroactive compounds. J. Biol. Chem. 292, 12934–12946. https://doi.org/10.1074/jbc.M117.794909
McCarthy, K.D., de Vellis, J., 1980. Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue. J. Cell Biol. 85, 890–902. McEwen, B.S., 1985. Steroids and brain function. Trends Pharmacol. Sci. 6, 22–26.
https://doi.org/10.1016/0165-6147(85)90011-2
Mellon, S.H., Deschepper, C.F., 1993. Neurosteroid biosynthesis: genes for adrenal steroidogenic enzymes are expressed in the brain. Brain Res. 629, 283–292.
Mensah-Nyagan, A.G., Kibaly, C., Schaeffer, V., Venard, C., Meyer, L., Patte- Mensah, C., 2008. Endogenous steroid production in the spinal cord and potential involvement in neuropathic pain modulation. J. Steroid Biochem. Mol. Biol., 12th International Congress on Hormonal Steroids and Hormones & Cancer - Part 2 (Athens, Greece, 13-16 September 2006) 109, 286–293. https://doi.org/10.1016/j.jsbmb.2008.03.002
Merhi, Z., Doswell, A., Krebs, K., Cipolla, M., 2014. Vitamin D alters genes involved in follicular development and steroidogenesis in human cumulus granulosa cells. J. Clin. Endocrinol. Metab. 99, E1137–1145. https://doi.org/10.1210/jc.2013-4161
Micevych, P.E., Chaban, V., Ogi, J., Dewing, P., Lu, J.K.H., Sinchak, K., 2007. Estradiol stimulates progesterone synthesis in hypothalamic astrocyte cultures. Endocrinology 148, 782–789. https://doi.org/10.1210/en.2006-0774
Millatt, L.J., Bocher, V., Fruchart, J.-C., Staels, B., 2003. Liver X receptors and the control of cholesterol homeostasis: potential therapeutic targets for the treatment of atherosclerosis. Biochim. Biophys. Acta BBA - Mol. Cell Biol. Lipids 1631, 107–118. https://doi.org/10.1016/S1388-1981(02)00366-9
Munro, A.W., Girvan, H.M., McLean, K.J., 2007. Variations on a (t)heme—novel mechanisms, redox partners and catalytic functions in the cytochrome P450 superfamily. Nat. Prod. Rep. 24, 585–609. https://doi.org/10.1039/B604190F Nebert, D.W., Gonzalez, F.J., 1987. P450 genes: structure, evolution, and
regulation. Annu. Rev. Biochem. 56, 945–993. https://doi.org/10.1146/annurev.bi.56.070187.004501
Nebert, D.W., Russell, D.W., 2002. Clinical importance of the cytochromes P450. Lancet Lond. Engl. 360, 1155–1162. https://doi.org/10.1016/S0140- 6736(02)11203-7
Nelson, D.R., 1999a. Cytochrome P450 and the Individuality of Species. Arch. Biochem. Biophys. 369, 1–10. https://doi.org/10.1006/abbi.1999.1352
Nelson, D.R., 1999b. A Second CYP26 P450 in Humans and Zebrafish: CYP26B1. Arch. Biochem. Biophys. 371, 345–347. https://doi.org/10.1006/abbi.1999.1438 Nelson, D.R., Zeldin, D.C., Hoffman, S.M.G., Maltais, L.J., Wain, H.M., Nebert,