To evaluate whether alterations in the multidrug-resistance (MDR)-1 gene correlate with intestinal MDR-1 expression and uptake of orally administered P-glycoprotein (PGP) substrates, we analyzed the MDR-1 sequence in 21 volunteers whose PGP expression and function in the duodenum had been determined by Western blots and quantitative immunohistology ( n = 21) or by plasma concentrations after orally administered digoxin ( n = 8 + 14). We observed a significant correlation of a polymorphism in exon 26 (C3435T) of MDR-1 with expression levels and function of MDR-1. Individuals homozygous for this polymorphism had significantly lower duodenal MDR-1 expression and the highest digoxin plasma levels. Homozygosity for this variant was observed in 24% of our sample population ( n = 188). This polymorphism is expected to affect the absorption and tissue concentrations of numerous other substrates of MDR-1.

This study provides the first analysis of MDR1 variant genotype distribution in a large sample of white subjects. It gives a basis for large-scale clinical investigations on the functional role of MDR1 allelic variants for bioavailability of a substantial number of drugs.

Deposition of the beta-amyloid peptide (Abeta) in the brain occurs during normal ageing and is substantially accelerated in patients with Alzheimer's disease. Since Abeta is continuously produced in the brain, it has been suggested that a clearance mechanism should exist to prevent its accumulation and subsequent aggregation. Until now, little attention has been paid to the possible role of P-glycoprotein (P-gp), a member of the ATP binding cassette superfamily of transporter proteins, in the pathogenesis of Alzheimer's disease. A recent study demonstrated that Abeta40 and Abeta42 interact directly with P-gp. We therefore hypothesized that Abeta accumulation in the brain would correlate inversely with the degree of vascular P-gp expression. To study early pathogenetic factors that influence the deposition of Abeta, at routine autopsies, brain tissue samples were taken from 243 non-demented subjects who died between the ages of 50 and 91 years. Vascular P-gp expression and the number of Abeta40- and Abeta42-positive senile plaques were assessed immunohistochemically in the medial temporal lobe. In addition, the apolipoprotein E (apoE) genotypes, as well as multiple drug resistance gene 1 ( ) polymorphisms (exon 2, G-1A; exon 21, G2677T/A; exon 26, C3436T), were also determined for each case. P-gp expression was not correlated with genotypes, but we found a significant inverse correlation between P-gp expression and the deposition of both Abeta40 and Abeta42 in the medial temporal lobe. Our results provide the first evidence in human brain tissue that the accumulation of Abeta may be influenced by the expression of P-gp in blood vessels, and suggest that P-gp may influence the elimination of Abeta from brain.

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Previous studies have yielded conflicting results as to the putative role of the functional polymorphism of the promoter region of the serotonin transporter gene (SLC6A4) in the etiology of anxiety-related traits and depressive disorders. Recently, a significant geneenvironment interaction was found between life stressors, the short allele of the SLC6A4 polymorphism and depression. The aim of the present study was to investigate if such a geneenvironment interaction could be replicated within a different population with a different risk structure. A total of 1005 subjects from a general population sample (Study of Health in Pomerania) were genotyped. Mental and physical distress were assessed on 38 items of the modified complaint scale (BL-38). The interaction between the SLC6A4 genotype, social stressors and chronic diseases with regard to the BL-38 score was evaluated by ANOVA. There was no independent association of genotype with mental and physical distress. However, significant interactions between genotype, unemployment and chronic diseases (F ¼ 6.6; df ¼ 3, 671; Po0.001) were found in females but not in males. The genotype explained 2% of the total variance of the BL-38 score and 9.1% of the explained variance. The results partly confirm previous findings of a significant gene-environment interaction of the short allele, indicating a higher mental vulnerability to social stressors and chronic diseases. The relevance of this finding is sustained by the fact that the sample characteristics and the risk structure were highly different from previous studies. Molecular Psychiatry (2005) 10, 220-224.

Amyloid-beta (Abeta) is the major component of the insoluble amyloid plaques that accumulate intracerebrally in patients with Alzheimer's disease (AD). It has been suggested that MDR1-P-glycoprotein (ABCB1, P-gp) plays a substantial role in the elimination of Abeta from the brain. In the present study, MDR1-transfected LLC cells growing in a polarized cell layer were used to characterize the interaction of Abeta1-40/1-42 with P-gp. In this system, P-gp-mediated transport can be followed by the efflux of the fluorescent dye rhodamine-123, or of Abeta itself from the cells into the apical extracellular space. Abeta significantly decreased the apical efflux of rhodamine-123, and the transcellular transport of Abeta1-40 and Abeta1-42 into the apical chamber could be demonstrated using both ELISA and fluorescence (FITC)-labeled peptides. This transport was inhibited by a P-gp modulator. Furthermore, ATP-dependent, P-gp-mediated transport of the fluorescence-labeled peptides could be demonstrated in isolated, inside-out membrane vesicles. Our data support the concept that P-gp is important for the clearance of Abeta from brain, and thus may represent a target protein for the prevention and/or treatment of neurodegenerative disorders such as AD.

Isoniazid is metabolized by the genetically polymorphic arylamine N-acetyltransferase type 2 (NAT2). A greater number of high-activity alleles are related to increased acetylation capacity and in some reports to low efficacy and toxicity of isoniazid. The objective of this study was to assess individual isoniazid exposure based on NAT2 genotype to predict a personalized therapeutic dose. Isoniazid was administered to 18 healthy Caucasians (age 30 ؎ 6 years, body weight 74 ؎ 10 kg, five women) in random order as a 200-mg infusion, a 100-mg oral, and a 300-mg oral single dose. For the assessment of NAT2 genotype, common single nucleotide polymorphisms identifying 99.9% of variant alleles were characterized. Noncompartmental pharmacokinetics and compartmental population pharmacokinetics were estimated from isoniazid plasma concentrations until 24 h postdose by high-pressure liquid chromatography. The influence of NAT2 genotype, drug formulation, body weight, and sex on dose-normalized isoniazid pharmacokinetics was assessed by analysis of variance from noncompartmental data and confirmed by population pharmacokinetics. Eight high-activity NAT2*4 alleles were identified. Sex had no effect; the other factors explained 93% of the variability in apparent isoniazid clearance (analysis of variance). NAT2 genotype alone accounted for 88% of variability. Individual isoniazid clearance could be predicted as clearance (liters/hour) ‫؍‬ 10 ؉ 9 ؋ (number of NAT2*4 alleles). To achieve similar isoniazid exposure, current standard doses presumably appropriate for patients with one high-activity NAT2 allele may be decreased or increased by approximately 50% for patients with no or two such alleles, respectively. Prospective clinical trials are required to assess the merits of this approach.