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PubMed2001

Production of a recombinant hybrid molecule of cholera toxin-B-subunit and proteolipid-protein-peptide for the treatment of experimental encephalomyelitis.

Mucosal administration of experimental autoimmune encephalomyelitis (EAE)-specific autoantigens can reduce the onset of disease. To examine whether cholera toxin-B-subunit (CTB)-conjugated EAE-specific T-cell epitope can reduce development of the autoimmune disease in mice, we produced a recombinant hybrid molecule of CTB fusion protein linked with proteolipid-protein (PLP)-peptide139-151(C140S) at levels up to 0.1 gram per liter culture media in Bacillus brevis as a secretion-expression system. Amino acid sequencing and GM1-receptor binding assay showed that this expression system produced a uniformed recombinant hybrid protein. EAE was induced in SJL/J mice by systemic administration with the PLP-peptide. When nasally immunized 5 times with 70 microg rCTB PLP-peptide hybrid protein, mice showed a significantly suppressed development of ongoing EAE and an inhibition of both the PLP-peptide-specific delayed-type hypersensitivity (DTH) responses and leukocyte infiltration into the spinal cord. In contrast, all mice given the PLP-peptide alone or the PLP-peptide with the free form of CTB did not suppress the development of EAE and DTH responses. These results suggest that nasal treatment with the recombinant B. brevis-derived hybrid protein of CTB and autoantigen peptide could prove useful in the control of multiple sclerosis.

Administration, Intranasal↗
PubMed2003

Structural and functional analysis of the killer element pPin1-3 from Pichia inositovora.

Strains of the yeast Pichia inositovora that carry the linear plasmids pPin1-1 (18 kb) and pPin1-3 (10 kb) display a killer activity towards Saccharomyces cerevisiae. Cloning and sequencing of the smaller plasmid, pPin1-3, revealed that it is 9683 bp long and has 154-bp terminal inverted repeats. Comparison of pPin1-3 with the only other completely sequenced killer plasmid, pGKL1 of Kluyveromyces lactis, revealed differences in genome organization. The Pichia element has four ORFs that account for 95% of the sequence. ORF1 is homologous to the putative immunity gene of the K. lactis system. A viral B-type DNA polymerase is encoded by ORF2. The predicted product of ORF3 displays similarities to the alpha- and beta-subunits of the heterotrimeric K. lactis killer toxin, also known as zymocin. A cysteine-rich chitin-binding site and a chitinase signature, characteristic for the alpha-subunit of zymocin were identified in Orf3p. Chitin affinity chromatography and Western analysis confirmed the plasmid specific expression and secretion of a protein that cross-reacts with an antibody raised against the alpha-subunit of K. lactis zymocin. Disruption of the major chitin synthase-gene ( CHS3) renders S. cerevisiae resistant to the toxin, providing further evidence that chitin is the cellular receptor for the P. inositovora toxin. Orf4p of pPin1-3 displays only weak similarities to the gamma-subunit of zymocin, which causes a G1 cell-cycle arrest in S. cerevisiae. However, disruption of the S. cerevisiae gene ELP3/TOT3, which encodes a histone-acetyltransferase that is essential for zymocin action, resulted in reduced sensitivity to the P. inositovora toxin also. Thus, despite obvious differences in genome organization and protein architecture, both killer systems very probably have similar modes of action.

Amino Acid Sequence↗
PubMed2003

Immune response induced by recombinant Mycobacterium bovis BCG producing the cholera toxin B subunit.

The pentameric form of the cholera toxin B subunit (CTB) is known to be a strong mucosal adjuvant and stimulates antigen-specific secretory immunoglobulin A (IgA) and systemic antibody responses to antigens when given by mucosal routes. To deliver CTB for prolonged periods of time to the respiratory mucosa, we constructed a Mycobacterium bovis bacillus Calmette-Guérin (BCG) strain that produces and secretes assembled pentameric CTB. Mice immunized intranasally (i.n.) with recombinant BCG (rBCG) developed a stronger anti-BCG IgA response in bronchoalveolar lavage fluids (BALF) than mice immunized with nonrecombinant BCG. The total IgA response in the BALF of mice immunized with rBCG was also stronger than that in BALF of mice immunized with the nonrecombinant strain. The induction of IgA was well correlated with an increased production of transforming growth factor beta1. Simultaneous administration of intraperitoneally delivered ovalbumin and of i.n. delivered CTB-producing BCG induced a long-lasting ovalbumin-specific mucosal IgA response as well as a systemic IgG response, both of which were significantly higher than those in mice immunized with nonrecombinant BCG together with ovalbumin. These results suggest that the CTB-producing BCG may be a powerful adjuvant to be considered for future mucosal vaccine development.

Adjuvants, Immunologic↗
PubMed1999

The Xanthomonas Hrp type III system secretes proteins from plant and mammalian bacterial pathogens.

Studies of essential pathogenicity determinants in Gram-negative bacteria have revealed the conservation of type III protein secretion systems that allow delivery of virulence factors into host cells from plant and animal pathogens. Ten of 21 Hrp proteins of the plant pathogen Xanthomonas campestris pv. vesicatoria have been suggested to be part of a type III machinery. Here, we report the hrp-dependent secretion of two avirulence proteins, AvrBs3 and AvrRxv, by X. campestris pv. vesicatoria strains that constitutively express hrp genes. Secretion occurred without leakage of a cytoplasmic marker in minimal medium containing BSA, at pH 5.4. Secretion was strictly hrp-dependent because a mutant carrying a deletion in hrcV, a conserved hrp gene, did not secrete AvrBs3 and AvrRxv. Moreover, the Hrp system of X. campestris pv. vesicatoria was able to secrete proteins from two other plant pathogens: PopA, a protein secreted via the Hrp system in Ralstonia solanacearum, and AvrB, an avirulence protein from Pseudomonas syringae pv. glycinea. Interestingly, X. campestris pv. vesicatoria also secreted YopE, a type III-secreted cytotoxin of the mammalian pathogen Yersinia pseudotuberculosis in a hrp-dependent manner. YerA, a YopE-specific chaperone, was required for YopE stability but not for secretion in X. campestris pv. vesicatoria. Our results demonstrate the functional conservation of the type III system of X. campestris for secretion of proteins from both plant and mammalian pathogens and imply recognition of their respective secretion signals.

Animals↗
PubMed1998

Initial binding of Shiga toxin-producing Escherichia coli to host cells and subsequent induction of actin rearrangements depend on filamentous EspA-containing surface appendages.

Shiga toxin-producing Escherichia coli (STEC) induce so-called attaching and effacing lesions that enable the tight adherence of these pathogens to the gut epithelium. All of the genes necessary for this process are present in the locus of enterocyte effacement, which encodes a type III secretion system, the secreted Esp proteins and the surface protein intimin. In this study we sequenced the espA gene of STEC, generated and characterized a corresponding deletion mutant and raised EspA-specific monoclonal antibodies to analyse the functional role of this protein during infection. EspA was detected in often filament-like structures decorating all bacteria that had attached to HeLa cells. These appendages were especially prominent on bacteria that had not yet induced the formation of actin pedestals, indicating that they mediate the initial contact of STEC to their target cells. Consistently, a deletion of the espA gene completely abolished the capacity of such STEC mutants to bind to HeLa cells and to induce actin rearrangements. Surface appendages similar to those described in this study are also formed by Pseudomonas syringae and may represent a structural element common to many bacterial pathogens that deliver proteins into their target cells via a type III secretion system.

Actins↗
PubMed1996

The proteolytic potential of normal human melanocytes: comparison with other skin cells and melanoma cell lines.

To understand the contribution of epidermal melanocytes in the proteolytic potential of human skin, we have studied melanocytes grown in a low-serum medium deprived of phorbol esters, cholera toxin, and other non-physiological supplements. We focused on the plasminogen activation system and certain matrix metalloproteinases (gelatinases). Supposing that the proteolytic activity of cells can influence binding to collagen matrix and its reorganization, we have analyzed these parameters as well. We found that human melanocytes secreted tissue-type plasminogen activator and utilised it to generate cell-bound plasmin. No urokinase-type plasminogen activator was detected in the cultures but its receptor was found in cell extracts. Both the 72 kDa and 92 kDa gelatinases were secreted by the cells and in equal amounts. In addition, melanocytes secreted the wide-spectrum proteinase inhibitor alpha-2-macroglobulin. Melanocytes cast into collagen matrices retained a rounded morphology, did not extend processes, and were unable to contract collagen lattices. As a control, these parameters were investigated in parallel in cultures of human keratinocytes, dermal fibroblasts, and two melanoma cell lines. The obtained characteristics suggest that normal human melanocytes are proteolytically active cells. This function may pertain to skin physiology and pathophysiology.

Cells, Cultured↗
PubMed2001

Production of Neisseria meningitidis transferrin-binding protein B by recombinant Bordetella pertussis.

Neisseria meningitidis serogroup B infections are among the major causes of fulminant septicemia and meningitis, especially severe in young children, and no broad vaccine is available yet. Because of poor immunogenicity of the serogroup B capsule, many efforts are now devoted to the identification of protective protein antigens. Among those are PorA and, more recently, transferrin-binding protein B (TbpB). In this study, TbpB of N. meningitidis was genetically fused to the N-terminal domain of the Bordetella pertussis filamentous hemagglutinin (FHA), and the fha-tbpB hybrid gene was expressed in B. pertussis either as a plasmid-borne gene or as a single copy inserted into the chromosome. The hybrid protein was efficiently secreted by the recombinant strains, despite its large size, and was recognized by both anti-FHA and anti-TbpB antibodies. A single intranasal administration of recombinant virulent or pertussis-toxin-deficient, attenuated B. pertussis to mice resulted in the production of antigen-specific systemic immunoglobulin G (IgG), as well as local IgG and IgA. The anti-TbpB serum antibodies were of the IgG1, IgG2a, and IgG2b isotypes and were found to express complement-mediated bactericidal activity against N. meningitidis. These observations indicate that recombinant B. pertussis may be a promising vector for the development of a mucosal vaccine against serogroup B meningococci.

Adhesins, Bacterial↗
PubMed2001

Macrophage migration inhibitory factor (MIF) modulates innate immune responses induced by endotoxin and Gram-negative bacteria.

Discovered in the early 1960s as a T-cell cytokine, MIF has emerged to be an important mediator of the innate immune system. MIF was identified recently to be released by a vast array of cells, including monocytes/macrophages, T-cells, B-cells, endocrine cells and epithelial cells in response to infection and stress. Bacteria, microbial toxins and cytokines have been shown to be powerful inducers of MIF secretion by macrophages. MIF stimulates the expression of pro-inflammatory mediators by immune cells and functions to counterbalance the anti-inflammatory and immunosuppressive effects of glucocorticoids. Like TNF and IL-1, MIF plays an important role in host responses to infection. Recombinant MIF was found to exacerbate lethal endotoxemia or bacterial sepsis when co-injected with LPS or Escherichia coli in mice. Conversely, MIF knockout mice or mice treated with anti-MIF antibodies were protected from shock induced by LPS, staphylococcal exotoxins or bacterial peritonitis, even when anti-MIF therapy was started after the onset of infection. Given the central role played by MIF in innate immune responses against microbial pathogens and in the regulation of inflammatory responses, pharmacological modulation of MIF production or neutralization of MIF activity could have broad clinical applications and may offer new treatment options for the management of patients with severe sepsis or septic shock.

Animals↗
PubMed1988

Neuroendocrine biomarkers of aging in the rat.

The genome and environmental agents are believed to regulate aging processes mainly via the homeostatic and integrative mechanisms of the body, which consist primarily of the neuroendocrine, immune and cell-to-cell communicating systems. Of these, the neuroendocrine system is considered to be the most important since it regulates to a greater or lesser degree all body functions, in old age as well as in early and mature life. We have studied mainly three aging events in the rat: the reproductive decline, development of numerous mammary and pituitary tumors and the decrease in GH secretion and protein synthesis. We have found that all three are caused primarily by faults that develop in hypothalamic function, particularly the decline in norepinephrine (NE) and dopamine (DA) activity. This decline appears to be caused largely by damage to hypothalamic neurons as a result of the chronic action of hormones, toxins, free radicals, cross linkages, lipofuscin accumulation and "wear and tear". Administration of drugs that increase hypothalamic NE and DA activity can delay or reverse all three aging events. Changes in hormone secretion, estrous cycles, tumor development and protein synthesis can be measured and used as "biomarkers of aging" in the rat.

Aging↗
PubMed1987

[Relation between glycoprotein synthesis and carbohydrate metabolism in the small intestine mucosa. Effect of cholera enterotoxin].

The regulatory properties of adenylate cyclase in small intestinal mucosa were investigated. Glucagon, epinephrine and isoproterenol failed to activate the cAMP synthesis; prostaglandin E1 caused a 2.8-fold, while cholera toxin-a 4.5-fold stimulation. The latter was not able to increase the rate of glucose synthesis from alanine in vitro, but increased markedly the in vivo incorporation of 14C-labeled alanine into the mucus glucosamine. Unlabeled glucosamine excretion was also enhanced 3-fold. This provides evidence for the involvement of glycolysis and gluconeogenesis enzyme systems in the mucosal glycoprotein synthesis. It was assumed that both metabolic pathways may play a common physiological role, namely, to convert carbohydrates and gluconeogenic precursors into the substrate for glucosamine synthesis which is thought to be a rate-limiting step in small intestinal mucus secretion.

Adenylyl Cyclase Inhibitors↗
PubMed1992

Barium and calcium stimulate secretion from digitonin-permeabilized bovine adrenal chromaffin cells by similar pathways.

We compared the characteristics of secretion stimulated by EGTA-buffered Ba(2+)- and Ca(2+)-containing solutions in digitonin-permeabilized bovine adrenal chromaffin cells. Half-maximal secretion occurred at approximately 100 microM Ba2+ or 1 microM Ca2+. Ba(2+)-stimulated release was not due to release of sequestered intracellular Ca2+ because at a constant free Ba2+ concentration, increasing unbound EGTA did not diminish the extent of release due to Ba2+. The maximal extents of Ba(2+)- and Ca(2+)-dependent secretion in the absence of MgATP were identical. MgATP enhanced Ba(2+)-induced secretion to a lesser extent than Ca(2+)-induced secretion. Half-maximal concentrations of Ba2+ and Ca2+, when added together to cells, yielded approximately additive amounts of secretion. Maximal concentrations of Ba2+ and Ca2+ when added together to cells for 2 or 15 min were not additive. Tetanus toxin inhibited Ba(2+)- and Ca(2+)-dependent secretion to a similar extent. Ba2+, unlike Ca2+, did not activate polyphosphoinositide-specific phospholipase C. These data indicate that (1) Ba2+ directly stimulates exocytosis, (2) Ba(2+)-induced secretion is stimulated to a lesser extent than Ca(2+)-dependent secretion by MgATP, (3) Ba2+ and Ca2+ use similar pathways to trigger exocytosis, and (4) exocytosis from permeabilized cells does not require activation of polyphosphoinositide-specific phospholipase C.

Adenosine Triphosphate↗
PubMed1991

In vitro induction of a Haemophilus influenzae type b polysaccharide-specific antibody response in human peripheral blood lymphocytes of individuals recently vaccinated with an oligosaccharide-protein conjugate.

In this paper an in vitro culture system for the induction of an antibody response to the Haemophilus influenzae type b polysaccharide (PRP) is described. Anti-PRP IgM and IgG antibody-secreting cells (ASC) and anti-diphtheria toxoid (DT) IgG ASC were detected in cultures of blood B and T cells derived from donors 4 to 6 wk after immunization with Haemophilus influenzae type b oligosaccharide-mutant diphtheria toxin (CRM197) conjugate (HbOC) and required in vitro restimulation with HbOC. When lymphocytes from HbOC-vaccinated donors were stimulated with PRP, anti-PRP IgM and IgG ASC could be detected in 50% offGe cases. Lymphocytes from PRP-vaccinated donors or non-vaccinated donors consistently failed to generate anti-PRP antibodies after in vitro stimulation with HbOC. Optimal in vitro responses were observed at concentrations of 0.06 to 0.6 micrograms/ml of Ag. At higher doses of Ag (6 micrograms/ml) anti-PRP and anti-DT antibody responses were suppressed. The in vitro generation of anti-PRP and anti-DT ASC, as detected by a spot-forming cell assay was shown to be T cell dependent, Ag dependent, and Ag specific. This culture system provides a model for the study of human B cell activation and immunoregulation by polysaccharide-protein conjugates and polysaccharides.

Adult↗
PubMed2000

Transcutaneous immunization induces mucosal and systemic immunity: a potent method for targeting immunity to the female reproductive tract.

Female BALB/c mice were immunized with tetanus toxoid (TT) admixed with cholera toxin by direct application to shaved skin (Transcutaneous immunization, TCI). Tetanus toxoid-specific IgG and IgA in serum, saliva, vaginal lavage and fecal pellets were assayed by ELISA. Tetanus toxoid specific antibody-secreting cell (ASC) numbers were also determined by immunohistochemistry in sections of vagina, uterus, salivary gland and small intestine of immunized mice. TCI elicited significant levels of TT-specific IgG in serum, saliva and vaginal lavage, with the greatest increases over background seen in saliva (80-400 fold) and vaginal lavage (2-87 fold). TCI induced only modest levels of IgA in any of the samples tested (range 2-7 fold increase). In the absence of cholera toxin, application of TT alone did not result in detectable TT-specific antibodies in mucosal secretions. ASCs were found in all tissues following TCI. Cells were most frequent in uterus and vaginal tissues with ASC numbers less frequent in small intestine and salivary gland. This suggests that local production, rather than transudation from serum, is a major contributor of antibody in reproductive tract secretions. Further studies focussed on the role of sex hormones and immune induction following TCI. Animals immunized at the stage of oestrus cycle at which estrogen is abundant (Estrus), showed significantly lower levels of TT-specific IgG in vaginal lavage samples. Collectively, these data confirm the findings of Glenn and colleagues (1998), who showed TCI using cholera toxin can elicit high levels of serum IgG to both the toxin and co-administered antigen and further demonstrates that this route of immunization is particularly effective at eliciting humoral immunity in saliva and in the female reproductive tract.

Animals↗
PubMed1996

Mucosal immune responses to intestinal bacterial pathogens.

Current advances in the study of gut mucosal immunology and molecular biology have enhanced our ability to understand the pathogenesis of enteric bacterial infections as well as the role of the immune system in mediating both tissue injury and protection. In this article, we review the immunopathogenesis and the protective immune response to three enteric pathogens, Vibrio cholerae, Shigella, and Salmonella. Each of these pathogens has a distinctive mechanism by which it causes disease, ie, epithelial attachment, epithelial invasion, and epithelial invasion with systemic dissemination. Pathogenicity and immune response can be conceptualized in terms of the interaction of these enteric pathogens with the gut epithelial compartment, immune inductive sites (Peyer's patch of the small intestine and lymphoid follicles of the colon), and a common immune effector compartment in the laimina propria where protective antibody is secreted. V cholerae, the representative noninvasive pathogen, has fimbrial adhesins that mediate attachment and colonization of the luminal surface of epithelial cells where organisms secrete cholera toxin (CT), a potent enterotoxin that induces a voluminous diarrhea via adenylate cyclase-dependent chloride secretion. Protective immunity is based on secretory (s) immunoglobulin A directed against whole-cell components that prevent attachment to gut epithelial cells and is enhanced by CT, an immunogen with potent adjuvant activity. Shigella, an enteric pathogen that locally invades gut epithelium, subverts the usual mechanism of immune sampling by initially invading via M cells overlying inductive sites. Subsequent macrophage invasion induces apoptosis and the release of interleukin-1, a proinflammatory cytokine. This seems to be a critical initiating event in immune-mediated tissue injury. Protective immunity is serotype specific. Infection caused by Salmonella is characterized by mucosal invasion and systemic spread mediated by the organisms ability to survive within macrophages. Both antibody and cell-mediated immunity are important for protection against Salmonella.

Antibodies, Bacterial↗
PubMed1997

Regulated secretion is impaired in AtT-20 endocrine cells stably transfected with botulinum neurotoxin type A light chain.

Botulinum neurotoxin type A (BoNT/A) inhibits neurotransmitter release by specific cleavage of SNAP-25, a synaptosome-associated protein also expressed in the ACTH secretory cell line AtT-20. Expression of light chain BoNT/A (L-BoNT/A) gene transfected into AtT-20 cells resulted in a cleaved form of SNAP-25 indistinguishable from that generated by bona fide BoNT/A. L-BoNT/A-transfected cells showed no difference in replication rate, viability, or phenotype, compared with control AtT-20 cells. In contrast, L-BoNT/A-transfected cells could not be induced to secrete ACTH upon stimulation by 8-bromo-cAMP or KCl. In addition, alpha-latrotoxin induced ACTH release from control cells, but not from L-BoNT/A-transfected cells. These experiments suggest an important role for SNAP-25 in regulated secretion from AtT-20 cells and underline the usefulness of this cell system as a tool for the study of the molecular mechanism of peptide hormone secretion.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2005

Implications of oxidative stress in the cytotoxicity of Pseudomonas aeruginosa ExoU.

ExoU PLA2-like activity has been shown to account for membrane lysis and acute death of infected cells. Translocation of effector proteins by the type III secretion systems depends on close contact between microbial and host cells. Our finding that both the ExoU-producing PA103 Pseudomonas aeruginosa and its mutant obtained by deletion of exoU adhered poorly to endothelial cells (EC) led to the hypothesis that, in some cells, the amount of injected toxin may not be enough to induce cell lysis but cells would suffer from a long-term effect of ExoU intoxication. To address this question, cells were exposed to both bacteria for 1 h and then treated with gentamicin-containing medium, to eliminate infecting microorganisms. After 24 h, the percentage of viable EC in PA103-infected cultures was significantly lower than in cultures exposed to the mutant, as determined by the MTT assay. Cell death was not likely to depend on the ExoU lytic activity since cell labeling with propidium iodide was similar in cultures infected with both bacterial strains. Bacterial cytotoxicity was significantly reduced by MAFP, a specific inhibitor of cPLA2 and iPLA2. Since the PLA2 activity on membrane phospholipids generates free fatty acid, including arachidonic acid (AA), we next compared the bacterial ability to release AA from infected EC. PA103 was shown to induce a potent AA release that was inhibited by MAFP. AA oxidation by oxygenases generates eicosanoids, known to induce both cell death and proliferation. However neither inhibitors of cyclooxygenases (ibuprofen) nor lipoxygenases (NDGA) reduced the ExoU toxicity. Since non-enzymatic oxidation of AA generates reactive radicals, we next investigated the PA103 ability to induce oxidative stress in infected cells. FACS analysis of cell labeling with the C-11 fluor probe and with anti-4-hydroxynonel antibody revealed a significant peroxidation of cell membrane lipids. These results, together with our finding that PA103-infected EC death was significantly attenuated by alpha-tocopherol, led to the conclusion that AA-induced oxidative stress may be another mechanism of cell damage in the course of infection by ExoU-producing P. aeruginosa.

Arachidonic Acid↗
PubMed2005

Effects of renal failure on drug transport and metabolism.

Renal failure not only alters the renal elimination, but also the non-renal disposition of drugs that are extensively metabolized by the liver. Although reduced metabolic enzyme activity in some cases can be responsible for the reduced drug clearance, alterations in the transporter systems may also be involved in the process. With the development of renal failure, the renal secretion of organic ions mediated by organic anion transporters (OATs) and organic cation transporters (OCTs) is decreased. 3-Carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) and other organic anionic uremic toxins may directly inhibit the renal excretion of various drugs and endogenous organic acids by competitively inhibiting OATs. In addition, the expression of OAT1 and OCT2 was reduced in chronic renal failure (CRF) rats. Renal failure also impairs the liver uptake of drugs and organic anions, such as bromosulphophthalein (BSP), indocyanine green (ICG), and thyroxine, where organic anion transport polypeptides (OATPs) are the major transporters. Most previous studies have been done in animals or cell culture, very often in rat models, but these are presumed to reflect the presentation of advanced renal disease in humans as well. Recent studies demonstrate that the uremic toxins CMPF and indoxyl sulfate (IS) can directly inhibit rOatp2 and hOATP-C in hepatocytes. The protein content of the liver uptake transporters Oatp1, 2, and 4 were significantly decreased in CRF rats. Decreased activity of the intestinal efflux transporter, P-glycoprotein (P-gp), was also observed in CRF rats, with no significant change of protein content, suggesting that uremic toxins may suppress P-gp function. However, increased protein levels of multidrug resistance-associated protein (MRP) 2 in the kidney and MRP3 in the liver were found in CRF rats, suggesting an adaptive response that may serve as a protective mechanism. Increases in drug areas under the curve (AUCs) in subjects with advanced renal disease for drugs that are not renally excreted are consistent with uremic toxin effects on either intestinal or hepatic cell transporters, metabolizing enzymes, or both. In conclusion, alterations of drug transporters, as well as metabolic enzymes, in patients with renal failure can be responsible for reduced drug clearance.

Animals↗