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Expression and Activity of Vitamin D-Metabolizing Cytochrome P450s (CYP1 and CYP24) in Human Nonsmall Cell Lung Carcinomas¹

Cytochroma, Inc. (G.J., H.R., A.Z., R.C., J.W., M.P.), Bioscience Complex, Kingston, Ontario, Canada K7L3N6; the Departments of Biochemistry (G.J., V.B., M.P.) and Medicine (G.J.); and Pathology and Cancer Research Laboratories (M.P.), Queen’s University, Kingston, Ontario, Canada K7L 3N6

Address all correspondence and requests for reprints to: Dr. Glenville Jones, Department of Biochemistry, Queen’s University, Kingston, Ontario, Canada K7L 3N6. E-mail: gj1{at}post.queensu.ca

Extrarenal 25-hydroxyvitamin D₃-1-hydroxylase is believed to play a major role in the pathogenesis of hypercalcemia associated with various types of granulomatous and lymphoproliferative diseases and certain solid tumors. In this paper, we describe the cloning of the cytochrome P450 component of the extrarenal enzyme from a human nonsmall cell lung carcinoma, SW 900. The cytochrome P450 for the extrarenal 1-hydroxylase has an amino acid sequence identical to that of the cytochrome P450 component of the CYP1, the renal form of the enzyme, and appears to be a product of the same gene. CYP1 messenger RNA (mRNA) and 1-hydroxylase enzyme activity were detected in two (SW 900, SK-Luci-6) of a series of five nonsmall cell lung carcinoma cell lines. All five lung cell lines were cultured with the same medium under the same conditions, but only two of the five expressed 1-hydroxylase enzyme; two others (WT-E, Calu-1) expressed high levels of the reciprocally regulated enzyme, 25-hydroxyvitamin D₃-24-hydroxylase, with its specific cytochrome P450 component, CYP24. Although under basal conditions the lung cell line SW 900 expressed only CYP1 and showed 1-hydroxylase enzyme activity, when treated with small concentrations of 1,25-dihydroxyvitamin D₃ or high concentrations of 25-hydroxyvitamin D₃, it began to express CYP24 and exhibit 24-hydroxylase enzyme activity. Somewhat surprisingly, SW 900 cells still had detectable CYP1 mRNA some 24 h after vitamin D treatment despite the fact that 1-hydroxylase enzyme activity was unmeasurable. These data are consistent with the emerging hypothesis that vitamin D through its active form does not directly turn off CYP1 mRNA production but, rather, strongly stimulates CYP24, thereby masking CYP1 activity. The factor(s) responsible for the basal expression of CYP1 in SW 900 and SK-Luci-6 is currently unknown.

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