Abstract
An important aspect of modern medicine is its orientation to achieve more personalized pharmacological treatments. In this context, transporters involved in drug disposition have gained well-justified attention. Owing to its broad spectrum of substrate specificity, including endogenous compounds and xenobiotics, and its strategical expression in organs accounting for drug disposition, such as intestine, liver and kidney, the SLC22 family of transporters plays an important role in physiology, pharmacology and toxicology. Among these carriers are plasma membrane transporters for organic cations (OCTs) and anions (OATs) with a marked overlap in substrate specificity. These two major clades of SLC22 proteins share a similar membrane topology but differ in their degree of genetic variability. Members of the OCT subfamily are highly polymorphic, whereas OATs have a lower number of genetic variants. Regarding drug disposition, changes in the activity of these variants affect intestinal absorption and target tissue uptake, but more frequently they modify plasma levels due to enhanced or reduced clearance by the liver and secretion by the kidney. The consequences of these changes in transport-associated function markedly affect the effectiveness and toxicity of the treatment in patients carrying the mutation. In solid tumors, changes in the expression of these transporters and the existence of genetic variants substantially determine the response to anticancer drugs. Moreover, chemoresistance usually evolves in response to pharmacological and radiological treatment. Future personalized medicine will require monitoring these changes in a dynamic way to adapt the treatment to the weaknesses shown by each tumor at each stage in each patient.
Highlights
Owing to its broad spectrum of substrate specificity and strategical expression in organs accounting for drug disposition, such as intestine, liver and kidney, the SLC22 family of human proteins plays an important role in physiology, pharmacology and toxicology (Figures 1 and 2)
Other organic cations (OCTs) and anions (OATs) have less pharmacological relevance, such as OAT6 (SLC22A20), which is mainly expressed in the olfactory mucosa, but not in the kidney and liver [81], and the SLC22A orphan (S22AO) (SLC22A24), the unkwown substrate transporter 6 (UST6) (SLC22A25) and organic cation transporter-like 2 (OCTL2) (SLC22A14) that are poorly known
In the time of emerging personalized medicine, it is becoming more evident that there is a need of, understanding the mechanisms of action and the profile of substrate specificity characteristic of each transporter involved in drug disposition, and identifying the genetic signature accounted for by the existence of polymorphisms that markedly determine the response of the patient to any given drug or combination of drugs
Summary
Owing to its broad spectrum of substrate specificity and strategical expression in organs accounting for drug disposition, such as intestine, liver and kidney, the SLC22 family of human proteins plays an important role in physiology, pharmacology and toxicology (Figures 1 and 2) This family includes 17 well-identified transporters, some orphan transporters and unassigned gene products, still to be fully characterized. The inside-negative plasma membrane potential facilitates the uptake of their substrates, which permits to achieve intracellular concentrations up to 10-fold higher than outside the cells [5] Phylogenetic studies of this gene subfamily suggest that it contains a clade formed by four plasma membrane transporters of carnitine (OCTN1, OCTN2, OCTN3 and OCT6).
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