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Vitamin D metabolis...
Vitamin D metabolism in osteoblast-like cells : effects of drugs on inactivation by CYP24A1
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- Zayny, Ahmad (author)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Steroid Biochemistry
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- Norlin, Maria (thesis advisor)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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- Wikvall, Kjell (thesis advisor)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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- Melhus, Håkan, Professor (opponent)
- Uppsala universitet,Institutionen för medicinska vetenskaper
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- Johansson, Inger (opponent)
- Department of Physiology and Pharmacology, Karolinska insitutet
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- Jerneren, Fredrik, Farm Dr (PhD) (opponent)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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(creator_code:org_t)
- Uppsala University, 2018
- English 33 s.
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Series: Licentiate theses / Faculty of Pharmacy, Uppsala University, 1400-6200 ; 50
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Abstract
Subject headings
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- Vitamin D is essential for bone function, and deficiency in active vitamin D hormone can lead to bone disorders. Long-term treatment with glucocorticoids and antiretroviral drugs used to treat HIV infection, results in osteoporosis and increased risk of fractures. Much remains unclear regarding the effects of these compounds in bone cells. In the current study, human osteosarcoma Saos-2 cells and primary human osteoblasts were found to express mRNA for the vitamin D receptor as well as activating and deactivating enzymes in vitamin D3 metabolism. These bone cells exhibited CYP24A1-mediated 24-hydroxylation, involved in deactivation of the active vitamin form. However, bioactivating vitamin D3 hydroxylase activities were not detected in either of these cells, indicating that local vitamin D bioactivation is not significant in osteoblasts.Several glucocorticoids and antiretroviral drugs, including prednisolone, efavirenz and ritonavir, down regulated CYP24A1 mRNA expression. Prednisolone and ritonavir also down regulated CYP24A1-mediated 24-hydroxylase activity in both Saos-2 and primary human osteoblasts.Also, prednisolone significantly suppressed a human CYP24A1 promoter-luciferase reporter gene in Saos-2 cells co-transfected with the glucocorticoid receptor. Thus, the results of the present study show suppression by glucocorticoids on CYP24A1 mRNA, CYP24A1-mediated metabolism and CYP24A1 promoter activity in human osteoblast-like cells. Interestingly, ritonavir markedly potentiated the induction of CYP24A1 mRNA expression by 1,25-dihydroxyvitamin D3 suggesting that ritonavir may have different regulatory effects depending on the vitamin D3 metabolite levelsAs part of this study, we examined if glucocorticoids are formed locally in Saos-2 cells. The experiments indicate formation of 11-deoxycortisol, a steroid with glucocorticoid activity, which can bind the glucocorticoid receptor. Our findings showing effects of glucocorticoids and antiretroviral drugs on CYP24A1 expression in human osteoblasts indicate a previously unknown mechanism for effects of glucocorticoids and antiretroviral drugs in human bone, where effects of these drugs may lead to altered levels of active vitamin D3.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
Keyword
- Pharmaceutical Biochemistry
- Farmaceutisk biokemi
- Pharmaceutical Biochemistry
- Farmaceutisk biokemi
Publication and Content Type
- vet (subject category)
- lic (subject category)
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