title: Regulation of human vitamin D(3) 25-hydroxylases in dermal fibroblasts and prostate cancer LNCaP cells.
abstract: In this study, we examined whether 1alpha,25-dihydroxyvitamin D(3) (calcitriol), phenobarbital, and the antiretroviral drug efavirenz, drugs used by patient groups with high incidence of low bone mineral density, could affect the 25-hydroxylase activity or expression of human 25-hydroxylases in dermal fibroblasts and prostate cancer LNCaP cells. Fibroblasts express the 25-hydroxylating enzymes CYP2R1 and CYP27A1. LNCaP cells were found to express two potential vitamin D 25-hydroxylases-CYP2R1 and CYP2J2. The presence in different cells of nuclear receptors vitamin D receptor (VDR), pregnane X receptor (PXR), and constitutive androstane receptor (CAR) was also determined. Phenobarbital suppressed the expression of CYP2R1 in fibroblasts and CYP2J2 in LNCaP cells. Efavirenz suppressed the expression of CYP2R1 in fibroblasts but not in LNCaP cells. CYP2J2 was slightly suppressed by efavirenz, whereas CYP27A1 was not affected by any of the two drugs. Calcitriol suppressed the expression of CYP2R1 in both fibroblasts and LNCaP cells but had no clear effect on the expression of either CYP2J2 or CYP27A1. The vitamin D(3) 25-hydroxylase activity in fibroblasts was suppressed by both calcitriol and efavirenz. In LNCaP cells, consumption of substrate (1alpha-hydroxyvitamin D(3)) was used as indicator of metabolism because no 1alpha,25-dihydroxyvitamin D(3) product could be determined. The amount of 1alpha-hydroxyvitamin D(3) remaining in cells treated with calcitriol was significantly increased. Taken together, 25-hydroxylation of vitamin D(3) was suppressed by calcitriol and drugs. The present study provides new information indicating that 25-hydroxylation of vitamin D(3) may be regulated. In addition, the current results may offer a possible explanation for the impaired bone health after treatment with certain drugs.
authors.affiliation: Department of Pharmaceutical Biosciences, University of Uppsala, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Ellfolk
authors.forename: Maria
authors.initials: M
authors.lastname: Norlin
authors.forename: Katarina
authors.initials: K
authors.lastname: Gyllensten
authors.forename: Kjell
authors.initials: K
authors.lastname: Wikvall
mesh_terms: D000480:Alkynes; D019380:Anti-HIV Agents / Q000009:adverse effects*; D000927:Anticonvulsants / Q000009:adverse effects*; D048588:Benzoxazines / Q000009:adverse effects*; D002117:Calcitriol / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D053493:Cholestanetriol 26-Monooxygenase / Q000096:biosynthesis*; D000090702:Constitutive Androstane Receptor; D003521:Cyclopropanes; D000090762:Cytochrome P-450 CYP2J2; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D000072467:Cytochrome P450 Family 2; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008297:Male; D010634:Phenobarbital / Q000009:adverse effects*; D000077297:Pregnane X Receptor; D011471:Prostatic Neoplasms; D018167:Receptors, Calcitriol / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis; D011987:Receptors, Steroid / Q000096:biosynthesis; D012867:Skin / Q000166:cytology; D014157:Transcription Factors / Q000096:biosynthesis
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D000927:Anticonvulsants; D048588:Benzoxazines; C000717350:CYP2J2 protein, human; D000090702:Constitutive Androstane Receptor; D003521:Cyclopropanes; D000077297:Pregnane X Receptor; D018167:Receptors, Calcitriol; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D003577:Cytochrome P-450 Enzyme System; D000090762:Cytochrome P-450 CYP2J2; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; C506833:CYP2R1 protein, human; C510163:CYP3A4 protein, human; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase; D002117:Calcitriol; C098320:efavirenz; D010634:Phenobarbital