MULTIDRUG RESISTANCE PROTEINS OF THE ABCC SUBFAMILY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 295

P-glycoprotein, in amino acid sequence and substrate specificity, the first mammalian
ATP-dependent drug efflux pump that had been identified. The ABCCs/MRPs vary
among each other with respect to substrate specificity, tissue distribution, and domain-
specific localization in polarized cells. Several ABCC/MRP subfamily members are
capable of conferring multidrug resistance. ABCC1, the first cloned ABCC/MRP sub-
family member, has been crystallized and resolved structurally, with a 22- A limit. 334
A higher resolution is expected in the future, which will give more insight into how
the transporter works at the molecular level.
The hereditary deficiency of ABCC2 leads to Dubin-Johnson syndrome, which
is characterized by conjugated hyperbilirubinemia, because bilirubin glucuronosides
cannot be secreted into bile. Although the hereditary deficiency of ABCC6 has been
identified as the molecular origin of pseudoxanthoma elasticum, a disease-relevant
physiological substrate of ABCC6 is currently unknown. It remains to be resolved
why the loss of a functional ABCC6 protein in hepatocytes and proximal tubule
epithelial cells of the kidney causes pathology in skin, eyes, and arteries.
The predominant localization of ABCCs/MRPs in liver, kidney, intestine, and
blood-tissue barriers shows that these transporters are important drug efflux pumps
determining the oral bioavailability of drugs, their distribution within the body, and
their elimination. In this context, naturally occurring sequence variants (i.e., single-
nucleotide polymorphisms) are of considerable clinical interest, because they may
affect drug disposition. However, functional analysis of the many known nonsyn-
onymous variants is just at the beginning and remains a challenging task for future
research.
Acknowledgments
The studies in the authors' laboratory were supported by the German Cancer Research
Center, Heidelberg, a collaboration between the German Cancer Research Center and
Pfizer Research Laboratories (Gorton, Connecticut), the German Research Founda-
tion (DFG), and the Wilhelm Sander-Stiftung, Munchen. We acknowledge the con-
tributions to this work from past and present members of our laboratory, particularly
Markus Buchler, Jorg Konig, Gabriele Jedlitschky, Inka Leier, Yunhai Cui, Verena
Keitel, Daniel Rost, Thomas Schaub, Wolfgang Hagmann, Hiroyki Tsujii, Young-Min
Lee, Miriam Bortfeld, Manuela Brom, Johanna Hummel-Eisenbeiss, Elke Herrmann,
and Daniela Keller, as well as the collaboration with Jurgen Kartenbeck and Herbert
Spring from the Cell Biology Division of the German Cancer Research Center.
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