Aldo D. Mottino

Consejo Nacional de Investigaciones Científicas y Técnicas

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Viviana A. Catania

Instituto de Fisiología Vegetal

Enrique J. Sánchez Pozzi

National University of Rosario

Marcelo G. Luquita

Consejo Nacional de Investigaciones Científicas y Técnicas

Silvina Stella Maris Villanueva

Consejo Nacional de Investigaciones Científicas y Técnicas

María Laura Ruiz

Consejo Nacional de Investigaciones Científicas y Técnicas

Mary Vore

University of Kentucky

Marcelo G. Roma

Consejo Nacional de Investigaciones Científicas y Técnicas

Juan Pablo Rigalli

University Hospital Heidelberg

Fernando A. Crocenzi

Consejo Nacional de Investigaciones Científicas y Técnicas

José M. Pellegrino

Instituto de Fisiología Vegetal

Cooperative Institutions

Consejo Nacional de Investigaciones Científicas y Técnicas

National University of Rosario

Instituto de Fisiología Vegetal

Institute of Physics Rosario

University of Buenos Aires

Instituto de Biología Molecular y Celular de Rosario

University of Kentucky

Centro Científico Tecnólogico - Rosario

Instituto de Cardiología y Cirugía Cardiovascular

Cornell University

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Biphasic modulation of cAMP levels by the contraceptive nomegestrol acetate. Impact on P-glycoprotein expression and activity in hepatic cells

Biochemical Pharmacology (2018)

Guillermo Nicolás Tocchetti Camila Juliana Domínguez Felipe Zecchinati Maite Rocío Arana María Laura Ruiz

P-glycoprotein

10.1016/j.bcp.2018.04.023

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Citations (3)

Effect of repeated administration with subtoxic doses of acetaminophen to rats on enterohepatic recirculation of a subsequent toxic dose

Biochemical Pharmacology (2009)

Carolina I. Ghanem María Laura Ruiz Silvina Stella Maris Villanueva Marcelo G. Luquita Susana Llesuy

Acetaminophen

Enterohepatic circulation

10.1016/j.bcp.2009.02.006

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Citations (40)

Protective role of unconjugated bilirubin on complement-mediated hepatocytolysis

Biochimica et Biophysica Acta (BBA) - General Subjects (2007)

Cecilia L. Basiglio Sandra Mónica María Arriaga Héctor F. Pelusa Adriana M. Almará Marcelo G. Roma

Unconjugated hyperbilirubinemia

Complement

10.1016/j.bbagen.2007.03.005

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Citations (23)

ABC Transporters in Extrahepatic Tissues: Pharmacological Regulation in Heart and Intestine

Current Medicinal Chemistry (2018)

Silvina Stella Maris Villanueva Wei Zhang Felipe Zecchinati Aldo D. Mottino Mary Vore

ATP binding cassette (ABC) transporters are transmembrane proteins expressed in secretory epithelia like the liver, kidneys and intestine, in the epithelia exhibiting barrier function such as the blood-brain barrier and placenta, and to a much lesser extent, in tissues like reproductive organs, lungs, heart and pancreas, among others. They regulate internal distribution of endogenous metabolites and xenobiotics including drugs of therapeutic use and also participate in their elimination from the body. We here describe the function and regulation of ABC transporters in the heart and small intestine, as examples of extrahepatic tissues, in which ABC proteins play clearly different roles. In the heart, they are involved in tissue pathogenesis as well as in protecting this organ against toxic compounds and druginduced oxidative stress. The small intestine is highly exposed to therapeutic drugs taken orally and, consequently, ABC transporters localized on its surface strongly influence drug absorption and pharmacokinetics. Examples of the ABC proteins currently described are Multidrug Resistance-associated Proteins 1 and 2 (MRP1 and 2) for heart and small intestine, respectively, and P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) for both organs.

Abcg2

P-glycoprotein

Multidrug Resistance-Associated Proteins

Solute carrier family

10.2174/0929867325666180327092639

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Citations (14)

HEPATIC AND EXTRAHEPATIC SYNTHESIS AND DISPOSITION OF DINITROPHENYL-S-GLUTATHIONE IN BILE DUCT-LIGATED RATS

Drug Metabolism and Disposition (2006)

Silvina Stella Maris Villanueva María Laura Ruiz Carol J. Soroka Shi‐Ying Cai Marcelo G. Luquita

The ability of the kidney and small intestine to synthesize and subsequently eliminate dinitrophenyl-S-glutathione (DNP-SG), a substrate for the multidrug resistance-associated proteins (Mrps), was assessed in bile duct-ligated (BDL) rats 1, 7, and 14 days after surgery, using an in vivo perfused jejunum model with simultaneous urine collection. A single i.v. dose of 30 μmol/kg b.wt. of 1-chloro-2,4-dinitrobenzene (CDNB) was administered, and its glutathione conjugate DNP-SG and dinitrophenyl cysteinyl glycine derivative, which is the result of γ-glutamyl-transferase action on DNP-SG, were determined in urine and intestinal perfusate by high-performance liquid chromatography. Intestinal excretion of these metabolites was unchanged at day 1, and decreased at days 7 and 14 (–39% and –33%, respectively) after surgery with respect to shams. In contrast, renal excretion was increased by 114%, 150%, and 128% at days 1, 7, and 14. Western blot studies revealed decreased levels of apical Mrp2 in liver and jejunum but increased levels in renal cortex from BDL animals, these changes being maximal between days 7 and 14. Assessment of expression of basolateral Mrp3 at day 14 postsurgery indicated preserved levels in renal cortex, duodenum, jejunum, distal ileum, and colon. Analysis of expression of glutathione-S-transferases α, μ, and π, as well as activity toward CDNB, indicates that formation of DNP-SG was impaired in liver, preserved in intestine, and increased in renal cortex. In conclusion, increased renal tubular conversion of CDNB to DNP-SG followed by subsequent Mrp2-mediated secretion into urine partially compensates for altered liver function in experimental obstructive cholestasis.

Dinitrophenyl

Disposition

10.1124/dmd.106.009415

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Citations (19)

Absence of hepatic p-nitrophenol UDP-glucuronosyltransferase induction by spironolactone in male rats: possible involvement of testosterone

Canadian Journal of Physiology and Pharmacology (1992)

Viviana A. Catania Marcelo G. Luquita Enrique J. Sánchez Pozzi Alejandro Ferri Aldo D. Mottino

This study was performed to determine whether the lack of spironolactone induction of hepatic p-nitrophenol UDP-glucuronosyltransferase in male rats could be attributed to a presumed interaction between spironolactone and testosterone. The effect of spironolactone was evaluated in four experimental groups: normal females, normal males, castrated males, and castrated males that received testosterone. Enzyme activity was measured in native microsomes and in microsomes activated with UDP-N-acetylglucosamine or Triton X-100. When the nucleotide was included in the incubations, it was observed that enzyme activity in castrated male rats decreased to values approaching those obtained in normal females. Treatment of castrated animals with testosterone enhanced enzyme activity so that no significant difference existed between this group and normal males. This suggests that testosterone may act as an endogenous inducer of hepatic p-nitrophenol glucuronidation. It was also found that only females and castrated males showed an increase in enzyme activity in response to spironolactone treatment. Thus, the absence of an additive effect of endogenous or exogenous testosterone and spironolactone on UDP-glucuronosyltransferase activity suggests that these compounds could share a common induction mechanism, which appears to reach its maximal capacity in male rats. Possible explanations of this observation are discussed. From the analysis of enzyme activity in native and Triton X-100 activated microsomes, it can be postulated that spironolactone enzyme induction in female and castrated male rats could be attributed to an enhancement in the transferase synthesis rather than to an alteration of the membrane environment.Key words: UDP-glucuronosytransferase, spironolactone, enzyme induction, testosterone, p-nitrophenol.

Glucuronosyltransferase

Microsoma

Inducer

10.1139/y92-213

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Citations (3)

Induction of Rat Intestinal P-glycoprotein by Spironolactone and Its Effect on Absorption of Orally Administered Digoxin

Journal of Pharmacology and Experimental Therapeutics (2006)

Carolina I. Ghanem Paula C. Gómez Marı́a C Arana Marı́a Perassolo Griselda Delli Carpini

The effect of the diuretic spironolactone (SL) on expression and function of intestinal P-glycoprotein (P-gp), as well as its impact on intestinal absorption of digoxin, was explored. Rats were treated with daily doses of 200 μmol/kg b.wt. of SL intraperitoneally for 3 consecutive days. The small intestine was divided into four equal segments of ∼25 cm, with segment I being the most proximal. Brush-border membranes were isolated and used in analysis of P-gp expression by Western blot analysis. P-gp content increased in the SL group by 526, 292, 210, and 622% over controls for segments I, II, III, and IV, respectively. Up-regulation of apical P-gp was confirmed by immunofluorescence microscopy. P-gp transport activity was explored in intestinal sacs prepared from segment IV using two different model substrates. Serosal to mucosal transport (efflux) of rhodamine 123 was 140% higher, and mucosal to serosal transport (absorption) of digoxin was 40% lower in the SL group, both indicating increased P-gp function. In vivo experiments showed that intestinal absorption of a single dose of digoxin administered p.o. was attenuated by SL pretreatment. Thus, concentration of digoxin in portal and peripheral blood was lower in SL versus control groups, as well as its accumulation in kidney and liver. Urinary excretion of digoxin was significantly decreased in the SL group, probably reflecting decreased systemic availability of digoxin for subsequent urinary elimination. We conclude that SL induces P-gp expression with potential impact on intestinal absorption of substrates with therapeutic application.

P-glycoprotein

10.1124/jpet.106.105668

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Citations (28)

Complement activation and disease: protective effects of hyperbilirubinaemia

Clinical Science (2009)

Cecilia L. Basiglio Sandra Mónica María Arriaga Fabián Pelusa Adriana M. Almará Jaime Kapitulnik

Complement, an important effector mechanism of the immune system, is an enzymatic cascade of approx. 30 serum proteins leading to the amplification of a specific humoral response. It can be activated through the classical or alternative pathways, or through the mannose-binding lectin pathway. The activation of the classical pathway is initiated by the binding of the C1 component to antigen-bound antibodies, known as immunocomplexes. C1 is a complex of one molecule of C1q, two molecules of C1r and two molecules of C1s. C1q contains three copies of a Y-shaped fundamental unit with globular heads included in its structure, which play a major role in the interaction with the Fc portion of immunoglobulins. Deficient or exacerbated activation of the complement system leads to diseases of variable severity, and pharmacological inhibition of the complement system is considered as a therapeutic strategy to ameliorate the inflammatory effects of exacerbated complement activation. Bilirubin is a product of haem degradation by the concerted action of haem oxygenase, which converts haem into biliverdin, and biliverdin reductase, which reduces biliverdin to UCB (unconjugated bilirubin). UCB exerts both cytoprotective and cytotoxic effects in a variety of tissues and cells, acting either as an antioxidant at low concentrations or as an oxidant at high concentrations. In the present review, we describe in detail the anti-complement properties of bilirubin, occurring at levels above the UCB concentrations found in normal human serum, as a beneficial effect of potential clinical relevance. We provide evidence that UCB interferes with the interaction between C1q and immunoglobulins, thus inhibiting the initial step in the activation of complement through the classical pathway. A molecular model is proposed for the interaction between UCB and C1q.

Biliverdin

Biliverdin reductase

Lectin pathway

Complement C1q

10.1042/cs20080540

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Citations (81)

ETHYNYLESTRADIOL INCREASES EXPRESSION AND ACTIVITY OF RAT LIVER MRP3

Drug Metabolism and Disposition (2006)

María Laura Ruiz Silvina Stella Maris Villanueva Marcelo G. Luquita Mary Vore Aldo D. Mottino

We evaluated the effect of ethynylestradiol (EE) administration (5 mg/kg b.wt. s.c., for 5 consecutive days) on the expression and activity of multidrug resistance-associated protein 3 (Mrp3) in rats. Western blotting analysis revealed decreased Mrp2 (-41%) and increased Mrp3 (+200%) expression by EE. To determine the functional impact of up-regulation of Mrp3 versus Mrp2, we measured the excretion of acetaminophen glucuronide (APAP-glu), a common substrate for both transporters, into bile and perfusate in the recirculating isolated perfused liver (IPL) model. APAP-glu was generated endogenously from acetaminophen (APAP), which was administered as a tracer dose (2 μmol/ml) into the perfusate. Biliary excretion of APAP-glu after 60 min of perfusion was reduced in EE-treated rats (-80%). In contrast, excretion into the perfusate was increased by EE (+45%). Liver content of APAP-glu at the end of the experiment was reduced by 36% in the EE group. The total amount of glucuronide remained the same in both groups. Taken together, these results indicate that up-regulation of Mrp3 led to an exacerbated basolateral versus canalicular excretion of conjugated APAP in IPL. We conclude that induced expression of basolateral Mrp3 by EE may represent a compensatory mechanism to prevent intracellular accumulation of common Mrp substrates, either endogenous or exogenous, due to reduced expression and activity of apical Mrp2.

10.1124/dmd.106.009316

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Citations (25)

Inhibition of rat liver microsomal bilirubin UDP-glucuronosyltransferase by ursodeoxycholic acid

Life Sciences (1994)

Enrique J. Sánchez Pozzi Marcelo G. Luquita Viviana A. Catania Emilio A. Rodríguez Garay Aldo D. Mottino

Ursodeoxycholic acid

Tauroursodeoxycholic acid

Chenodeoxycholic acid

Deoxycholic acid

Glucuronosyltransferase

Glycocholic acid

10.1016/0024-3205(94)90102-3

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Citations (11)