The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/9/797/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 5, September 7, 1998 797-808

Articles

Multidrug Resistance Protein 1 Protects the Oropharyngeal Mucosal Layer and the Testicular Tubules against Drug-induced Damage

Jan Wijnholds*, George L. Scheffer||, Martin van der Valk{ddagger}, Paul van der Valk||, Jos H. Beijnen§, Rik J. Scheper||, and Piet Borst*

From the * Division of Molecular Biology and the {ddagger} Department of Experimental Animal Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam; the § Department of Pharmacy, Slotervaart Hospital, 1066 EC Amsterdam; and the || Department of Pathology, Free University Hospital, 1081 HV Amsterdam, The Netherlands

The multidrug resistance protein 1 (MRP1) gene encodes a transporter protein that helps to protect cells against xenobiotics. Elevated levels of MRP1 in tumor cells can result in active extrusion of a wide range of (anticancer) drugs with different cellular targets, a phenomenon called multidrug resistance (MDR). To explore the protective function of the mouse mrp1 protein during drug treatment, we investigated the toxicity caused by the anticancer drug etoposide-phosphate (ETOPOPHOS) in mice lacking the mrp1 gene (mrp1–/– mice). We show here that the lack of mrp1 protein results in increased etoposide-induced damage to the mucosa of the oropharyngeal cavity and to the seminiferous tubules of the testis. The high concentrations of mrp1 that we find in the basal layers of the oropharyngeal mucosa and in the basal membrane of the Sertoli cells in the testis apparently protect wild-type mice against this tissue damage. We also find drug-induced polyuria in mrp1–/– mice, which correlates with the presence of mrp1 protein in the urinary collecting tubules, the major site of kidney water reabsorption. Our results indicate that specific inhibitors of MRP1 used to reverse MDR, in combination with carcinostatic drugs transported by MRP1, might lead to drug-induced mucositis, (temporary) infertility, and diabetes insipidus.

Key Words: etoposide • multidrug resistance protein 1 • mucositis • polyuria • blood–testis barrier

Address correspondence to Piet Borst, Division of Molecular Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Phone: 131-20-5122880; Fax: 131-20-6691383.

Abbreviations used: cMOAT and cmoat, human and mouse canalicular multispecific organic anion transporter, respectively; ETOPOPHOS, etoposide-phosphate; FeNa, fractional excretion of sodium; GFR, glomerular filtration rate; GS-X, glutathione S-conjugate; LTC4, leukotriene C4; MDR, multidrug resistance; MDR1 and mdr1, human and mouse multidrug resistance gene 1, respectively; MRP1 and mrp1, human and mouse multidrug resistance protein 1, respectively; Pgp, P-glycoprotein; RFI, renal failure index; UCr and PCr, urine and plasma creatinine.


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