Phosphorous Dysregulation Induced by MEK Small Molecule Inhibitors in the Rat Involves Blockade of FGF-23 Signaling in the Kidney

被引：19

作者：

Diaz, Dolores ^{[1
]}

Allamneni, Krishna ^{[1
]}

Tarrant, Jacqueline M. ^{[1
]}

Lewin-Koh, Sock-Cheng ^{[2
]}

Pai, Rama ^{[1
]}

Dhawan, Preeti ^{[1
]}

Cain, Gary R. ^{[1
]}

Kozlowski, Cleopatra ^{[1
]}

Hiraragi, Hajime ^{[1
]}

La, Nghi ^{[1
]}

Hartley, Dylan P. ^{[1
]}

Ding, Xiao ^{[3
]}

Dean, Brian J. ^{[3
]}

Bheddah, Sheila ^{[4
]}

Dambach, Donna M. ^{[1
]}

机构：

[1] Genentech Inc, Safety Assessment, San Francisco, CA 94080 USA

[2] Genentech Inc, Biostat, San Francisco, CA 94080 USA

[3] Genentech Inc, Drug Metab & Pharmacokinet, San Francisco, CA 94080 USA

[4] Genentech Inc, Res Pathol, San Francisco, CA 94080 USA

来源：

TOXICOLOGICAL SCIENCES | 2012年 / 125卷 / 01期

关键词：

MEK inhibitor; mineralization; phosphorousdysregulation; elevated vitamin D; FGF-23; PTH; NaPiIIa; VITAMIN-D METABOLISM; IN-VIVO; PHOSPHATE; FGF23; EXPRESSION; CLONING; KLOTHO; FIBROBLAST-GROWTH-FACTOR-23; TRANSPORTER; DISCOVERY;

D O I：

10.1093/toxsci/kfr263

中图分类号：

R99 [毒物学（毒理学）];

学科分类号：

100405 [卫生毒理学];

摘要：

MEK, a kinase downstream of Ras and Raf oncogenes, constitutes a high priority target in oncology research. MEK small molecule inhibitors cause soft tissue mineralization in rats secondary to serum inorganic phosphorus (iP) elevation, but the molecular mechanism for this toxicity remains undetermined. We performed investigative studies with structurally distinct MEK inhibitors GEN-A and PD325901 (PD-901) in Sprague-Dawley rats. Our data support a mechanism that involves FGF-23 signal blockade in the rat kidney, causing transcriptional upregulation of 25-hydroxyvitamin D-3 1-alpha-hydroxylase (Cyp27b1), the rate-limiting enzyme in vitamin D activation, and downregulation of 1,25-dihydroxyvitamin D-3 24-hydroxylase (Cyp24a1), the enzyme that initiates the degradation of the active form of vitamin D. These transcriptional changes increase serum vitamin D levels, which in turn drive the increase in serum iP, leading to soft tissue mineralization in the rat.

引用

页码：187 / 195

页数：9

共 28 条

[1]

Agresti A, 2013, Categorical data analysis, V3rd

[2]

[Anonymous], 2004, Applied Longitudinal Analysis

[3]

Hormonal regulation of 25-hydroxyvitamin D3-lα-hydroxylase and 24-hydroxylase gene transcription in opossum kidney cells [J].

Armbrecht, HJ ;

Hodam, TL ;

Boltz, MA .

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 2003, 409 (02) :298-304

[4]

Specific regulation of CYP27B1 and VDR in proximal versus distal renal cells [J].

Bajwa, Amandeep ;

Forster, Megan N. ;

Maiti, Aparna ;

Woolbright, Benjamin L. ;

Beckman, Matthew J. .

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 2008, 477 (01) :33-42

[5]

Targeted inactivation of Npt2 in mice leads to severe renal phosphate wasting, hypercalciuria, and skeletal abnormalities [J].

Beck, L ;

Karaplis, AC ;

Amizuka, N ;

Hewson, AS ;

Ozawa, H ;

Tenenhouse, HS .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (09) :5372-5377

[6]

The parathyroid is a target organ for FGF23 in rats [J].

Ben-Dov, Iddo Z. ;

Galitzer, Hillel ;

Lavi-Moshayoff, Vardit ;

Goetz, Regina ;

Kuro-o, Makoto ;

Mohammadi, Moosa ;

Sirkis, Roy ;

Naveh-Many, Tally ;

Silver, Justin .

JOURNAL OF CLINICAL INVESTIGATION, 2007, 117 (12) :4003-4008

[7]

CONTROLLING THE FALSE DISCOVERY RATE - A PRACTICAL AND POWERFUL APPROACH TO MULTIPLE TESTING [J].

BENJAMINI, Y ;

HOCHBERG, Y .

JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES B-STATISTICAL METHODOLOGY, 1995, 57 (01) :289-300

[8]

Brown A. P., 2005, TOXICOLOGIST, V90, P108

[9]

Brown A. P., 2010, BIOMARKERS DRUG DEV, P301

[10]

MOLECULAR-CLONING, FUNCTIONAL EXPRESSION, TISSUE DISTRIBUTION, AND IN-SITU HYBRIDIZATION OF THE RENAL SODIUM-PHOSPHATE (NA+/P-I) TRANSPORTER IN THE CONTROL AND HYPOPHOSPHATEMIC MOUSE [J].

COLLINS, JF ;

GHISHAN, FK .

FASEB JOURNAL, 1994, 8 (11) :862-868

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