Peter Meier | Werqwer - Academia.edu (original) (raw)

Papers by Peter Meier

Annual Review of Physiology, 2002

Bile salts are the major organic solutes in bile and undergo extensive enterohepatic circulation.... more Bile salts are the major organic solutes in bile and undergo extensive enterohepatic circulation. Hepatocellular bile salt uptake is mediated predominantly by the Na(+)-taurocholate cotransport proteins Ntcp (rodents) and NTCP (humans) and by the Na(+)-independent organic anion-transporting polypeptides Oatp1, Oatp2, and Oatp4 (rodents) and OATP-C (humans). After diffusion (bound by intracellular bile salt-binding proteins) to the canalicular membrane, monoanionic bile salts are secreted into bile canaliculi by the bile salt export pump Bsep (rodents) or BSEP (humans). Both belong to the ATP-binding cassette (ABC) transporter superfamily. Dianionic conjugated bile salts are secreted into bile by the multidrug-resistance-associated proteins Mrp2/MRP2. In bile ductules, a minor portion of protonated bile acids and monomeric bile salts are reabsorbed by non-ionic diffusion and the apical sodium-dependent bile salt transporter Asbt/ASBT, transported back into the periductular capillary plexus by Mrp3/MRP3 [and/or a truncated form of Asbt (tAsbt)], and subjected to cholehepatic shunting. The major portion of biliary bile salts is aggregated into mixed micelles and transported into the intestine, where they are reabsorbed by apical Oatp3, the apical sodium-dependent bile salt transporter (ASBT), cytosolic intestinal bile acid-binding protein (IBABP), and basolateral Mrp3/MRP3 and tAsbt. Transcriptional and posttranscriptional regulation of these enterohepatic bile salt transporters is closely related to the regulation of lipid and cholesterol homeostasis. Furthermore, defective expression and function of bile salt transporters have been recognized as important causes for various cholestatic liver diseases.

Clinical Pharmacology & Therapeutics, 2001

BackgroundDuring clinical trials bosentan, the first orally active endothelin receptor antagonist... more BackgroundDuring clinical trials bosentan, the first orally active endothelin receptor antagonist, caused asymptomatic transaminase elevations in some patients. In this study we investigated whether inhibition of the hepatocanalicular bile salt export pump (rodents, Bsep; humans, BSEP ABCB11) could account for bosentan-induced liver injury.During clinical trials bosentan, the first orally active endothelin receptor antagonist, caused asymptomatic transaminase elevations in some patients. In this study we investigated whether inhibition of the hepatocanalicular bile salt export pump (rodents, Bsep; humans, BSEP ABCB11) could account for bosentan-induced liver injury.MethodsWe reanalyzed the safety database of the bosentan trials for cholestatic liver injury, determined the cholestatic potency of bosentan in the rat, and studied the effects of bosentan and its metabolites on Bsep-mediated taurocholate transport in vitro.We reanalyzed the safety database of the bosentan trials for cholestatic liver injury, determined the cholestatic potency of bosentan in the rat, and studied the effects of bosentan and its metabolites on Bsep-mediated taurocholate transport in vitro.ResultsBosentan caused dose-dependent and reversible liver injury in 2% to 18% of patients and caused a significant increase of serum bile salt levels (P < .01). Concomitant administration of glyburide (INN, glibenclamide) enhanced the cholestatic potency of bosentan. Similar effects were seen in rats, in which serum bile salt levels were increased by glyburide less than by bosentan, which increased the levels less than a combination of bosentan and glyburide. In vitro, Bsep-mediated taurocholate transport was inhibited by bosentan (inhibition constant, ≈12 μmol/L) and metabolites (inhibition constant, ≈8.5 μmol/L for metabolite Ro 47–8634).Bosentan caused dose-dependent and reversible liver injury in 2% to 18% of patients and caused a significant increase of serum bile salt levels (P < .01). Concomitant administration of glyburide (INN, glibenclamide) enhanced the cholestatic potency of bosentan. Similar effects were seen in rats, in which serum bile salt levels were increased by glyburide less than by bosentan, which increased the levels less than a combination of bosentan and glyburide. In vitro, Bsep-mediated taurocholate transport was inhibited by bosentan (inhibition constant, ≈12 μmol/L) and metabolites (inhibition constant, ≈8.5 μmol/L for metabolite Ro 47–8634).ConclusionThese results indicate that bosentan-induced liver injury is mediated, at least in part, by inhibition of Bsep/BSEP–causing intracellular accumulation of cytotoxic bile salts and bile salt induced liver cell damage. The data further emphasize the pathophysiologic importance of drug-Bsep interactions in acquired forms of cholestatic liver injury.Clinical Pharmacology & Therapeutics (2001) 69, 223–231; doi: 10.1067/mcp.2001.114667These results indicate that bosentan-induced liver injury is mediated, at least in part, by inhibition of Bsep/BSEP–causing intracellular accumulation of cytotoxic bile salts and bile salt induced liver cell damage. The data further emphasize the pathophysiologic importance of drug-Bsep interactions in acquired forms of cholestatic liver injury.Clinical Pharmacology & Therapeutics (2001) 69, 223–231; doi: 10.1067/mcp.2001.114667

Pflugers Archiv-european Journal of Physiology, 2004

The organic anion transporting polypeptides (rodents: Oatps, human: OATPs) form a superfamily of ... more The organic anion transporting polypeptides (rodents: Oatps, human: OATPs) form a superfamily of sodium-independent transport systems that mediate the transmembrane transport of a wide range of amphipathic endogenous and exogenous organic compounds. Since the traditional SLC21 gene classification does not permit an unequivocal and species-independent identification of genes and gene products, all Oatps/OATPs are newly classified within the OATP/SLCO superfamily and subdivided into families (≥40% amino acid sequence identity), subfamilies (≥60% amino acid sequence identity) and individual genes and gene products according to their phylogenetic relationships and chronology of identification. Implementation of this new classification and nomenclature system occurs in agreement with the HUGO Gene Nomenclature Committee (HGNC). Among 52 members of the OATP/SLCO superfamily, 36 members have been identified so far in humans, rat and mouse. The latter are clustered within 6 (out of 12) families (OATP1–OATP6) and 13 subfamilies. Oatps/OATPs represent 12 transmembrane domain proteins and contain the superfamily signature D-X-RW-(I,V)-GAWW-X-G-(F,L)-L. Although species divergence, multispecificity and wide tissue distribution are common characteristics of many Oatps/OATPs, some members of the OATP/SLCO superfamily are highly conserved during evolution, have a high substrate specificity and exhibit unique cellular expression in distinct organs. Hence, while Oatps/OATPs with broad substrate specificity appear to play an important role in the bioavailability, distribution and excretion of numerous exogenous amphipathic organic anionic compounds, Oatps/OATPs with a narrow spectrum of transport substrates may exhibit more specific physiological functions in distinct organs.

Proceedings of The National Academy of Sciences, 1991

Liver parenchymal cells continuously extract high amounts of bile acids from portal blood plasma.... more Liver parenchymal cells continuously extract high amounts of bile acids from portal blood plasma. This uptake process is mediated by a Na+/bile acid cotransport system. A cDNA encoding the rat liver bile acid uptake system has been isolated by expression cloning in Xenopus laevis oocytes. The cloned transporter is strictly sodium-dependent and can be inhibited by various non-bile-acid organic compounds. Sequence analysis of the cDNA revealed an open reading frame of 1086 nucleotides coding for a protein of 362 amino acids (calculated molecular mass 39 kDa) with five possible N-linked glycosylation sites and seven putative transmembrane domains. Translation experiments in vitro and in oocytes indicate that the transporter is indeed glycosylated and that its polypeptide backbone has an apparent molecular mass of 33-35 kDa. Northern blot analysis with the cloned probe revealed crossreactivity with mRNA species from rat kidney and intestine as well as from liver tissues of mouse, guinea pig, rabbit, and man.

Gastroenterology, 2001

Abbreviations used in this paper: BSP, bromosulphophthalein; cRNA, complementary RNA; DHEAS, dehy... more Abbreviations used in this paper: BSP, bromosulphophthalein; cRNA, complementary RNA; DHEAS, dehydroepiandrosterone sulfate; DPDPE, [D-penicillamine 2,5 ]enkephalin; E 2 17␤G, estradiol-17␤glucuronide; Lst-1/LST-1, rat/human liver-specific transporter 1; LTC 4 , leukotriene C 4 ; OAT-K1, rat kidney organic anion transporter; Oatp/ OATP, rat/human organic anion-transporting polypeptide; PCR, polymerase chain reaction; PGE 2 , prostaglandin E 2 ; Pgt/PGT, rat/human prostaglandin transporter; T 3 , triiodothyronine; T 4 , thyroxine.

Gastroenterology, 2000

Abbreviations used in this paper: Bsep (BSEP), bile salt export pump of rat (human) liver; cLPM, ... more Abbreviations used in this paper: Bsep (BSEP), bile salt export pump of rat (human) liver; cLPM, canalicular liver plasma membrane; CyA, cyclosporin A; E 2 17G, ethinylestradiol-17␤-glucuronide; MDR, multidrug resistance gene product; MOI, multiplicity of infection; Mrp2 (MRP2), canalicular multidrug resistance protein 2 of rat (human) liver; PFIC, progressive familial intrahepatic cholestasis.

Proceedings of The National Academy of Sciences, 1994

Seminars in Liver Disease, 2000

Clinical Pharmacology & Therapeutics, 2000

St John's Wort (hypericum perforatum) is an herbal medicine that is frequently used for t... more St John's Wort (hypericum perforatum) is an herbal medicine that is frequently used for therapy of mild depression. Recently, St John's Wort was reported to substantially decrease blood/plasma concentrations and efficacy of cyclosporine (INN, ciclosporin), indinavir, and digoxin. In this study we investigated the mechanisms of these St John's Wort-induced drug interactions. In a preclinical study, the administration of St John's Wort extract to rats during 14 days resulted in a 3.8-fold increase of intestinal P-glycoprotein/Mdrl expression and in a 2.5-fold increase in hepatic CYP3A2 expression (Western blot analyses). In a clinical study, the administration of St John's Wort extract to 8 healthy male volunteers during 14 days resulted in an 18% decrease of digoxin exposure after a single digoxin dose (0.5 mg), in 1.4- and 1.5-fold increased expressions of duodenal P-glycoprotein/MDR1 and CYP3A4, respectively, and in a 1.4-fold increase in the functional activity of hepatic CYP3A4 (14C-erythromycin breath test). These results indicate direct inducing effects of St John's Wort on intestinal P-glycoprotein/MDR1 (in rats and humans), hepatic CYP3A2 (in rats), and intestinal and hepatic CYP3A4 (in humans). Therefore the results provide a mechanistic explanation for the previously observed drug interactions in patients and support the importance of intestinal P-glycoprotein/MDR1 in addition to intestinal and hepatic CYP3A4 for overall drug absorption and disposition in humans.

Gastroenterology, 1995

Background & Aims: Based on a recently cloned rat liver organic anion transporter, we attempt... more Background & Aims: Based on a recently cloned rat liver organic anion transporter, we attempted to clone the corresponding human liver organic anion transporting polypeptide. Methods: A human liver complementary DNA library was screened with a specific rat liver complementary DNA probe. The human liver transporter was cloned by homology with the rat protein and functionally characterized in Xenopus laevis

Hepatology, 1994

To characterize the transport functions of a recently cloned basolateral organic anion transporti... more To characterize the transport functions of a recently cloned basolateral organic anion transporting polypeptide of rat hepatocytes we performed further kinetic transport and substrate cis-inhibition studies in organic anion-transporting polypeptide—cRNA injected Xenopus laevis oocytes. The studies demonstrate saturable Na+-independent sulfobromophthalein (Michaelis-Menten constant, 1.5 μmol/L) and taurocholate (Michaelis-Menten constant, 50 μmol/L) uptake by organic anion-transporting polypeptide. Sulfobromophthalein uptake was inhibited by the following organic anions: 0.01 mmol/L bilirubin (43%), 0.1 mmol/L indocyanine green (81%), 0.1 mmol/L 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid (DIDS; 52%) and 1 mmol/L probenecid (74%). Competitive inhibition was shown for indocyanine green (inhibition constant about 1.3 μmol/L). Sulfobromophthalein and taurocholate uptakes were also inhibited by cholate, chenodeoxycholate, deoxycholate and ursodeoxycholate, as well as their glycine and taurine conjugates. Organic anion-transporting polypeptide also mediated uptake of glycocholate, tauroursodeoxycholate and taurochenodeoxycholate. No cis-inhibition of sulfobromophthalein uptake was seen in the presence of ATP, para-aminohippuric acid, bumetanide, digitoxin, reduced glutathione, leukotriene C4, nicotinic acid, ouabain, oxalate, rifampicin, succinate or sulfate. Furthermore, radioactively labeled paraaminohippuric acid, α-ketoglutarate and reduced glutathione were not taken up by organic aniontransporting polypeptide in cRNA-injected frog oocytes. These data confirm that organic aniontransporting polypeptide represents a novel hepatocellular organic anion uptake system that can mediate Na+-independent transport of monovalent (e.g., bile acids) and divalent (e.g., sulfobromophthalein and indocyanine green) cholephilic organic anions. A variety of substrates previously shown to inhibit uptake of sulfobromophthalein and bile acids in perfused rat livers, isolated hepatocytes and basolateral membrane vesicles had no cis-inhibitory effects on organic aniontransporting polypeptide—mediated organic anion transport in X. laevis oocytes. Thus additional Na+-independent organic anion carriers must be present in the basolateral membranes of rat hepatocytes. (Hepatology 1994;20:411-416.)

Gastroenterology, 1999

Background & Aims: Multispecific organic anion-transporting polypeptides (Oatps) are involved in ... more Background & Aims: Multispecific organic anion-transporting polypeptides (Oatps) are involved in the transcellular movement of amphipathic compounds in many tissues including the liver, kidney, and blood-brain barrier. Recently, a high-affinity digoxin transporter (Oatp2) was cloned from rat brain and shown to be also expressed in the liver. Methods: We investigated the cellular and subcellular distribution of Oatp2 in rat liver by in situ hybridization technology and immunofluorescence microscopy and compared its substrate specificity with that of Oatp1 in complementary RNA-injected Xenopus laevis oocytes. Results: The results show a selective basolateral (sinusoidal) expression of Oatp2 in midzonal to perivenous hepatocytes, but not in periportal or the innermost layer of perivenous hepatocytes. Common substrates of both Oatp1 and Oatp2 include bile salts, steroid conjugates, thyroid hormones (T3, T4), ouabain, and the endothelin receptor antagonist BQ-123 (Michaelis constants: Oatp1, D600 mol/L; Oatp2, D30 mol/L). Other organic anions including sulfolithotaurocholate, bilirubin monoglucuronide, and sulfobromophthalein were transported only by Oatp1. Conclusions: These results provide definite evidence for the partially overlapping and partially selective substrate specificities of Oatp1 and Oatp2. The unique acinar distribution of Oatp2 might indicate that it represents a high-affinity ''backup'' system for complete hepatocellular removal of certain cholephilic substances from portal blood plasma.

Proceedings of The National Academy of Sciences, 1997

A novel multispecific organic anion transporting polypeptide (oatp2) has been isolated from rat b... more A novel multispecific organic anion transporting polypeptide (oatp2) has been isolated from rat brain. The cloned cDNA contains 3,640 bp. The coding region extends over 1,983 nucleotides, thus encoding a polypeptide of 661 amino acids. Oatp2 is homologous to other members of the oatp gene family of membrane transporters with 12 predicted transmembrane domains, five potential glycosylation, and six potential protein kinase C phosphorylation sites. In functional expression studies in Xenopus laevis oocytes, oatp2 mediated uptake of the bile acids taurocholate (K m Ϸ 35 M) and cholate (K m Ϸ 46 M), the estrogen conjugates 17␤estradiol-glucuronide (K m Ϸ 3 M) and estrone-3-sulfate (K m Ϸ 11 M), and the cardiac gylcosides ouabain (K m Ϸ 470 M) and digoxin (K m Ϸ 0.24 M). Although most of the tested compounds are common substrates of several oatp-related transporters, high-affinity uptake of digoxin is a unique feature of the newly cloned oatp2. On the basis of Northern blot analysis under high-stringency conditions, oatp2 is highly expressed in brain, liver, and kidney but not in heart, spleen, lung, skeletal muscle, and testes. These results provide further support for the overall significance of oatps as a new family of multispecific organic anion transporters. They indicate that oatp2 may play an especially important role in the brain accumulation and toxicity of digoxin and in the hepatobiliary and renal excretion of cardiac glycosides from the body.