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Published online on March 14, 2000, 10.1073/pnas.050585397
PNAS | March 28, 2000 | vol. 97 | no. 7 | 3473-3478


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Vol. 97, Issue 7, 3473-3478, March 28, 2000

Medical Sciences
 Functional polymorphisms of the human multidrug-resistance gene: Multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo

(cancer therapy / drug resistance / molecular transport / pharmacogenetics)

S. Hoffmeyer*, O. Burkdagger , O. von Richterdagger , H. P. Arnold*, J. BrockmöllerDagger , A. JohneDagger , I. CascorbiDagger , T. GerloffDagger , I. RootsDagger , M. Eichelbaumdagger , and U. Brinkmann*,§

* Epidauros Biotechnology, Pharmacogenetics Laboratory, Am Neuland 1, D-82347 Bernried, Germany; dagger  Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstrasse 112, D-70376 Stuttgart, Germany; and Dagger  Institute of Clinical Pharmacology, University Medical Center Charité, Humboldt University, Schumannstrasse 20, D-10098 Berlin, Germany

Communicated by Ira Pastan, National Institutes of Health, Bethesda, MD, December 31, 1999 (received for review November 23, 1999)

To evaluate whether alterations in the multidrug-resistance (MDR)-1 gene correlate with intestinal MDR-1 expression and uptake of orally administered P-glycoprotein (PGP) substrates, we analyzed the MDR-1 sequence in 21 volunteers whose PGP expression and function in the duodenum had been determined by Western blots and quantitative immunohistology (n = 21) or by plasma concentrations after orally administered digoxin (n = 8 + 14). We observed a significant correlation of a polymorphism in exon 26 (C3435T) of MDR-1 with expression levels and function of MDR-1. Individuals homozygous for this polymorphism had significantly lower duodenal MDR-1 expression and the highest digoxin plasma levels. Homozygosity for this variant was observed in 24% of our sample population (n = 188). This polymorphism is expected to affect the absorption and tissue concentrations of numerous other substrates of MDR-1.

§ To whom reprint requests should be addressed. E-mail: uli{at}epidauros.com.


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