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Biomedical subjects

Christiane Pauli-Magnus

Publications and source records attributed to Christiane Pauli-Magnus.

5 recordsLinked to original sources
PubMed2003

Pharmacogenetics of hepatocellular transporters.

One of the main functions of the liver is the production of bile and the biliary secretion of endogenous and exogenous substances, including drugs and drug metabolites. Bile formation is a complex sequence of cellular events, which involves uptake of bile constituents and xenobiotics on the basolateral (sinusoidal) plasma membrane of hepatocytes and secretion of cholephilic compounds across the apical (canalicular) membrane. These uptake and efflux processes are maintained by distinct transport systems expressed at the two polar surface domains of liver cells. Any functional disturbance of these canalicular transport systems can lead to cholestatic liver disease, which is associated with intracellular accumulation of toxic bile constituents and consecutive cholestatic liver cell damage. Interaction of drugs with hepatobiliary transport systems is increasingly recognized as cause of acquired cholestatic syndromes. Thereby, genetically determined alterations of hepatobiliary transporter functions are important risk factors for an individual's susceptibility to develop cholestasis. Especially, mutations in canalicular transporter genes can cause certain forms of hereditary cholestatic liver disease, including progressive familial intrahepatic cholestasis or intrahepatic cholestasis of pregnancy. In addition, systematic genetic screenings have discovered numerous single nucleotide polymorphisms in hepatobiliary transporter genes that lead to amino acid exchanges in the encoded proteins. However, the functional consequences and the clinical relevance of most of these polymorphisms remain to be defined. This overview summarizes the physiological function of human hepatobiliary transport systems and discusses the impact of their genetic variations for the pathophysiology of cholestatic syndromes and the pharmacogenetics of drug-induced cholestasis.

ATP-Binding Cassette Transporters↗
PubMed2003

Sequence diversity and haplotype structure in the human ABCB1 (MDR1, multidrug resistance transporter) gene.

OBJECTIVES: There is increasing evidence that polymorphism of the ABCB1 (MDR1) gene contributes to interindividual variability in bioavailability and tissue distribution of P-glycoprotein substrates. The aim of the present study was to (1) identify and describe novel variants in the ABCB1 gene, (2) understand the extent of variation in ABCB1 at the population level, (3) analyze how variation in ABCB1 is structured in haplotypes, and (4) functionally characterize the effect of the most common amino acid change in P-glycoprotein. METHODS AND RESULTS: Forty-eight variant sites, including 30 novel variants and 13 coding for amino acid changes, were identified in a collection of 247 ethnically diverse DNA samples. These variants comprised 64 statistically inferred haplotypes, 33 of which accounted for 92% of chromosomes analyzed. The two most common haplotypes, ABCB1*1 and ABCB1*13, differed at six sites (three intronic, two synonymous, and one non-synonymous) and were present in 36% of all chromosomes. Significant population substructure was detected at both the nucleotide and haplotype level. Linkage disequilibrium was significant across the entire ABCB1 gene, especially between the variant sites found in ABCB1*13, and recombination was inferred. The Ala893Ser change found in the common ABCB1*13 haplotype did not affect P-glycoprotein function. CONCLUSION: This study represents a comprehensive analysis of ABCB1 nucleotide diversity and haplotype structure in different populations and illustrates the importance of haplotype considerations in characterizing the functional consequences of ABCB1 polymorphisms.

Base Sequence↗
PubMed2000

Naltrexone does not relieve uremic pruritus: results of a randomized, double-blind, placebo-controlled crossover study.

Improvement of uremic pruritus was reported under short-term administration of the mu-receptor antagonists naltrexone and naloxone. The aim of the present study was to confirm the efficacy and safety of the oral mu-receptor antagonist naltrexone during a 4-wk treatment period in patients on hemodialysis and peritoneal dialysis. A placebo-controlled, double-blind crossover study of uremic patients with persistent, treatment-resistant pruritus was performed. Of 422 patients screened between December 1997 and June 1998, 93 suffered from pruritus and 23 were eligible for the study. Patients were started either with a 4-wk naltrexone sequence (50 mg/d) or matched placebo. This was followed by a 7-d washout, and patients continued with a 4-wk sequence of the alternate medication. Pruritus intensity was scored daily by a visual analogue scale (VAS) and weekly by a detailed score assessing scratching activity, distribution of pruritus, and frequency of pruritus-related sleep disturbance. Sixteen of 23 patients completed the study. During the naltrexone period, pruritus decreased by 29.2% (95% confidence interval [CI], 18.7 to 39.6) on the VAS and by 17.6% (95% CI, 4.2 to 31.1) on the detailed score. In comparison, pruritus decreased by 16.9% (95% CI, 6.8 to 26.9) on the VAS and by 22.3% (95% CI, 9.3 to 35.2) on the detailed score during the placebo period. The difference between the naltrexone and the placebo treatment period was not statistically significant. Nine of 23 patients complained of gastrointestinal disturbances during the naltrexone period compared with only one of 23 patients during the placebo period (P < 0.05). These results show that treatment of uremic pruritus with naltrexone is ineffective. In addition, a high incidence of adverse effects was observed during treatment with naltrexone.

Administration, Oral↗