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Regulation of Human Vitamin D₃ 25-Hydroxylases in Dermal Fibroblasts and Prostate Cancer LNCaP Cells

Department of Pharmaceutical Biosciences, Division of Biochemistry, University of Uppsala, Uppsala, Sweden (M.E., M.N., K.W.); and Infectious Disease Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden (K.G.)

In this study, we examined whether 1,25-dihydroxyvitamin D₃ (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 D₃ 25-hydroxylase activity in fibroblasts was suppressed by both calcitriol and efavirenz. In LNCaP cells, consumption of substrate (1-hydroxyvitamin D₃) was used as indicator of metabolism because no 1,25-dihydroxyvitamin D₃ product could be determined. The amount of 1-hydroxyvitamin D₃ remaining in cells treated with calcitriol was significantly increased. Taken together, 25-hydroxylation of vitamin D₃ was suppressed by calcitriol and drugs. The present study provides new information indicating that 25-hydroxylation of vitamin D₃ may be regulated. In addition, the current results may offer a possible explanation for the impaired bone health after treatment with certain drugs.

Received for publication November 24, 2008.

Accepted for publication March 11, 2009.

Address correspondence to: Kjell Wikvall, Department of Pharmaceutical Biosciences, Division of Biochemistry, Box 578, University of Uppsala, SE-751 23 Uppsala, Sweden. E-mail: kjell.wikvall{at}farmbio.uu.se