title: Drug-Mediated Gene Regulation of Vitamin D3Metabolism in Primary Human Dermal Fibroblasts.
abstract: Vitamin D metabolism was studied in primary human dermal fibroblasts with focus on drug-mediated gene regulation related to adverse side effects of antiretroviral drugs used in HIV therapy. The fibroblasts expressed mRNA for cytochrome P450 (CYP) enzymes catalysing bioactivating (CYP2R1, CYP27A1 and CYP27B1) and catabolic reactions (CYP24A1). The cells produced both 25-hydroxyvitamin D3and 1α,25-dihydroxyvitamin D3. The results demonstrate that primary dermal fibroblasts have an active vitamin D3-metabolizing system. High incidence of low bone mineral density is a concern for HIV-infected patients treated with antiretroviral drugs. Osteomalacia and severe vitamin D deficiency have been reported. We investigated whether drug-mediated gene regulation could be a possible mechanism behind these adverse drug effects. Fibroblasts were treated with different drugs used in HIV therapy, and the 1α,25-dihydroxyvitamin D3levels and relative mRNA levels for crucial enzymes were determined. Efavirenz, stavudine and ritonavir significantly down-regulated the bioactivating CYP2R1 and up-regulated the catabolic CYP24A1. The drugs reduced bioactivating enzyme activities and cellular levels of 1α,25-dihydroxyvitamin D3. The current results indicate that effects on gene expression may lead to disturbed vitamin D metabolism and decreased cellular levels of active vitamin D3. The data are consistent with the impaired bone health in patients treated with certain antiretroviral drugs.
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Norlin
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Lundqvist
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Ellfolk
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Maritta
authors.initials: M
authors.lastname: Hellström Pigg
authors.affiliation: Department of Women's and Children's Health, Uppsala University, University Children's Hospital, Uppsala, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Gustafsson
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: Kjell
authors.initials: K
authors.lastname: Wikvall
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000494:pharmacology*; D048588:Benzoxazines / Q000494:pharmacology; D002112:Calcifediol / Q000378:metabolism; D002117:Calcitriol / Q000037:antagonists & inhibitors / Q000378:metabolism; D002478:Cells, Cultured; D002762:Cholecalciferol / Q000378:metabolism*; D053493:Cholestanetriol 26-Monooxygenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D003521:Cyclopropanes; D000072467:Cytochrome P450 Family 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020405:Dermis / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D015203:Reproducibility of Results; D019438:Ritonavir / Q000494:pharmacology; D018119:Stavudine / Q000494:pharmacology; D065668:Vitamin D3 24-Hydroxylase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D012333:RNA, Messenger; D002762:Cholecalciferol; D018119:Stavudine; D000072467:Cytochrome P450 Family 2; C506833:CYP2R1 protein, human; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; C000600378:CYP27B1 protein, human; D002117:Calcitriol; C098320:efavirenz; D019438:Ritonavir; D002112:Calcifediol