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Editorial

Editorial overview

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Pages 654-655 | Published online: 22 Sep 2008

The issue of acquired resistance to therapeutic treatment has been known for decades. Reports of resistance to therapeutic intervention in both humans (Burrows Citation1931) and pathogens (Carpenter et al. Citation1945) led to a concerted effort to both understand, and mitigate, this issue. Initially, much research focussed on the induction/inhibition of metabolic enzymes, but recently the spotlight has fallen on the role of drug transport proteins. These proteins act as gateways to the body and its organs, determining xenobiotic disposition throughout the system. To date, drug transport proteins having been identified in all organisms from E.coli to H.sapiens (Annilo et al. Citation2006; Hagenbuch and Meier Citation2004), highlighting their evolutionary importance for survival, with a multitude of transporters having been identified in both humans (Annilo et al. Citation2006; Hagenbuch and Meier Citation2004) and pathogens (Johnson et al. Citation2008; Thornewell et al. Citation1997).

The identification of drug transport proteins and the realisation of their vital role in acquired resistance to xenobiotic treatment, have placed drug transporter proteins on the same level as metabolic enzymes with regard to their importance in ADME. Reviews in this special issue examine their impact both at the level of drug development (Morgan and Ayrton) and for regulatory submissions (Huang).

As with any rapidly developing field, the nomenclature of drug transport proteins can quickly confuse the uninitiated, and even those within the field! Mammalian drug transport proteins can be broadly divided into the SLC family, which are characterised as facilitative of secondary active transporters of solutes, and the ABC family, which are defined by the presence of an ATP-Binding Cassette within their structure, and act as primary active transporters. Through a series of reviews in this edition, the major sub-families of the SLC and ABC transporters are described, along with their roles in xenobiotic transport.

In parallel with the drug metabolising enzymes, drug transport proteins also play an important role in endogenous metabolism; indeed, the dysregulation of endogenous metabolism through xenobiotic intervention may represent an important class of adverse drug reactions. Papers by Graham; Karpen and Kosters and Patel examine the role of drug transport proteins in endogenous physiological processes, highlighting how xenobiotic-mediated effects on transporters can impact upon these processes.

Finally, the realisation that drug transport proteins are of major importance in the discovery, development and safe marketing of xenobiotics has meant that novel methodologies are required to allow their study. Both in silico (Wainer) and in vitro (Elsby, Surry, Smith and Gray) approaches to investigate drug transport proteins are discussed in this special issue.

With the advent of systems biology it has become clear that to understand, and predict, whole body responses it is necessary to understand the complex network of interactions that occur within the body (Plant Citation2004). The role that drug transporters play in these networks, acting as both entry and exit portals, as well as influencing overall body disposition of xenobiotics means that appreciation of these systems is a major component to increased understanding of xenobiotic action.

References

  • Annilo T, Chen ZQ, Shulenin S, Costantino J, Thomas L, Lou H, Stefanov S, Dean M. Evolution of the vertebrate ABC gene family: Analysis of gene birth and death. Genomics 2006; 88(1)1–11
  • Burrows H. Tumour resistance. Journal of Pathology and Bacteriology 1931; 34(6)802–3
  • Carpenter CM, Bahn JM, Ackerman H, Stokinger HE. Adaptability of Gonococcus to 4 bacteriostatic agents, sodium sulfathiazole, rivanol lactate, promin, and penicillin. Proceedings of the Society for Experimental Biology and Medicine 1945; 60(1)168–71
  • Hagenbuch B, Meier PJ. Organic anion transporting polypeptides of the OATP/SLC21 family: Phylogenetic classification as OATP/SLCO superfamily, new nomenclature and molecular/functional properties. Pflugers Archiv-European Journal of Physiology 2004; 447(5)653–65
  • Johnson DJ, Owen A, Plant N, Bray PG, Ward SA. Drug-regulated gene expression of Plasmodium falciparum P-glycoprotein homologue 1: A putative role for nuclear receptors. Antimicrobial Agents and Chemotherapy 2008; 52(4)1438–45
  • Plant N. Interaction networks: Coordinating responses to xenobiotic exposure. Toxicology 2004; 202: 21–32
  • Thornewell SJ, Peery RB, Skatrud PL. Cloning and characterization of CneMDR1: A Cryptococcus neoformans gene encoding a protein related to multidrug resistance proteins. Gene 1997; 201(1–2)21–9

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