Resultados y discusión

The tissue distribution of transporters has been studied using different techniques. Consistent with their potential role in detoxification processes and physiological functions, transporters are expressed in various tissues as demonstrated in human normal tissues as well as in human cancer cell lines.

Certain transporters show a more restricted tissue expression pattern (MDR3, BSEP, OATP-A, OATP-C, and OATP8) while others can be detected in almost every tissue that has been investigated (e.g., MDR1, OATP-B, OATP-D, and OATP-E). This indicates that some transporters have organ-specific functions while others might be involved in more housekeeping functions.

Intestines

P-gp is expressed in the luminal membrane of intestinal mucosal epithelium.

Several efflux pumps such as BCRP, MRP2, and MRP4 are also highly expressed in the intestinal mucosal epithelial cells. However, some of MRPs are expressed at basolateral membrane of intestinal epithelium, such as MRP1, MRP3, and MRP5 (Fig. 1). The abundance of P-gp expression varies in different intestinal sections. The expression of P-gp increases with distance. (The lowest amount of P-gp is located in stomach, highest in colon, and medium in jejunum/ileum [61], exactly opposite to the expression of CYP3A4/5.) CYP3A4/5 expression decreases longitudinally [62].

FIGURE 1 Schematic representation of selected ABC transporters in the intestinal membrane.

Liver

Liver is an important organ for metabolism of numerous endogenous and exogenous compounds, a process in which many transporters are involved.

Hepatic uptake of organic anions, cations, and bile salts is supported by transporters in the basolateral (sinusoidal) membranes of hepatocytes including OATPs, OATs, and OCTs. ATP-binding cassette transporter proteins in the canalicular membranes of hepatocytes mediate the hepatic efflux of drugs, bile salts, and metabolites against a steep concentration gradient from liver to bile, which includes the MDR1 and MDR3, MRP2, and BSEP. However, MDR3 is mainly responsible for the transport of endogenous phospholipids though a recent report indicated that MDR3 may transport some drugs [63]. These transporters play essential roles in transporting, metabolizing, and excretion of bile salts, xenobiotics, and environmental toxins (Fig. 2).

Kidney

Multiple organic anion transporters play important roles in the elimination of a variety of endogenous and exogenous compounds, and their metabolites from the body. Several families of multispecific organic anion transporters mediating the renal elimination of organic anions have been identified. Members of the organic anion transporter (OAT), organic anion transporting polypeptide (OATP), multidrug resistance protein (MRP),

FIGURE 2 Schematic representation of selected drug transporters in hepatocytes.

sodium–phosphate transporter (NPT), and peptide transporter (PEPT) families have been identified in the renal proximal tubules. Uptake of organic anions (OA^–) across the basolateral membranes of renal epithelial cells followed by efflux into urine across the apical membrane is mediated by the Na⁺-dependent organic transporter, OAT1 and the Na⁺-independent organic transporter, perhaps OAT3. The function of MRP6 at the basolateral membrane is unknown. Efflux across the apical membrane of organic anions is through low-affinity anion exchange and/or facilitated diffusion, and a Na⁺-independent ATP-driven system. The luminal membrane contains various efflux transporter proteins including OATK1/

K2, OAT4, NPT, MRP2, and MRP4. The luminal membrane also contains various uptake transporters such as OATP1, PEPT 1/2 (Fig. 3).

Brain

The brain is protected against drugs and toxins by the two drug-permeability barriers: the BBB and the blood–cerebrospinal fluid (CSF) barrier (BCSFB). The BBB is primarily formed by the endothelium of the blood capillaries in the brain. P-gp is expressed in the luminal plasma membrane of capillary endothelial cells and plays a significant role in restricting the brain permeability of drugs [64].

FIGURE 3 Schematic representation of selected renal drug transporters.

P-gp is expressed to a great extent in the apical (luminal) plasma membranes of these capillary endothelial cells, conferring an apical-to-basal transepithelial permeation barrier to drugs. MRP1 localizes basolaterally, conferring an opposing basal-to-apical drug-permeation barrier. Together, these transporter proteins may coordinate secretion and reabsorption of endogenous substrates and therapeutic drugs into and out of the central nervous system [65].

Recently, some other transporter proteins including MRPs, OATP, and OAT have been also reported to exist in the BBB and the BCFSB [66, 67].

Placenta

P-gp is expressed at the brush border membrane of the syncytiotrophoblast.

The expression appears to be higher early in gestation compared with term placenta [68, 69]. Absence or pharmacological inhibition of placental P-gp profoundly increases fetal drug exposure. Intravenous administration of radioactive digoxin, saquinavir, and paclitaxel to pregnant dams resulted in 2.4-, 7-, or 16-fold more drug in fetuses with mdrla (-/-)(-/-) 1b (-/-)(-/-) than the wild-type fetuses. Placental P-gp could be completely inhibited by PSC833 or GG918 when given to heterozygous dams indicating that the placental drug-transporting P-gp is of great importance in limiting the fetal penetration of various potentially harmful or therapeutic compounds, and demonstrate that this P-gp function can be abolished by pharmacological means [70].

The mRNA levels of various transporters in rat placenta were assessed during late-stage pregnancy. Sixteen mRNAs of various transporters were expressed in placenta at concentrations similar to or higher than that in maternal liver and kidney. They include Mdrla and 1b, Mrpl, Mrp5, Oct3 and Octn1, Oatp3, and oatp 12 [71]. The abundance of these mRNA transcripts in placenta suggests a role for these transporters in placental transport of endogenous and exogenous compounds. In human placenta, OATP-B has been detected in the trophoblast at the basal membranes where it may play a role in transporting natural substrates (e.g., steroid hormone conjugates) from the fetal circulation into the trophoblast [72].