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Background: An association between the 677C>T polymorphism (rs1801133) in the methylenetetrahydrofolate reductase gene (MTHFR) and cluster headache is plausible, but has not been investigated., Objective: To investigate this association among Caucasians., Methods: Case-control study among 147 cluster headache patients and 599 population-based age- and gender-matched controls. Cluster headache was diagnosed according to the criteria of the International Headache Society. Genotypes of the MTHFR 677C>T polymorphism were detected by restriction fragment length polymorphism analysis. We used logistic regression analysis to investigate the association between cluster headache and genotypes with additive, dominant, and recessive models. We considered a Bonferroni-corrected P value <.004 as significant., Results: Mean age at study entry among patients was 44.9 years (SD 11.4), of whom 76.2% were men. The genotype distribution among controls and patients was in Hardy-Weinberg equilibrium. The genotype and allele distribution did not differ between patients with any cluster headache and controls. We also did not find an association when assuming additive, dominant or recessive genetic models. When we looked at subgroups, the effect estimates suggested an increased risk for chronic cluster headache (dominant model: odds ratio = 2.82; 99.6% confidence interval = 0.72-11.07; P = .03)., Conclusions: Data from our case-control study do not indicate an association between genotypes of the MTHFR 677C>T polymorphism and cluster headache overall. Subgroup analyses suggested that carriers of the MTHFR 677T allele may have an increased risk for chronic cluster headache. This may be regarded as hypothesis-generating and should be further investigated in independent studies., (© 2010 American Headache Society.)

Background: The cardiac effects of statins are subject to controversial discussion, and the mechanism of their uptake into the human heart is unknown. A candidate protein is the organic anion transporting polypeptide (OATP) 2B1 (SLCO2B1), because related transporters are involved in the uptake of statins into the human liver. In this study we examine OATP2B1 expression in the human heart and describe statins as inhibitors and substrates of OATP2B1., Methods: The expression of OATP2B1 was analyzed in 46 human atrial and 15 ventricular samples, including samples from hearts with dilated cardiomyopathy and hearts with ischemic cardiomyopathy., Results: Significant messenger ribonucleic acid expression was found in all samples, with no difference in the diseased hearts. However, patients who had taken atorvastatin exhibit decreased OATP2B1 messenger ribonucleic acid expression compared with patients with no statin treatment. OATP2B1 protein was detected at approximately 85 kd in atrial samples, as well as ventricular samples, and could be localized to the vascular endothelium. Furthermore, estrone-3-sulfate transport into OATP2B1-overexpressing Madin-Darby canine kidney II cells was inhibited by various drugs, including atorvastatin, simvastatin, cerivastatin, glyburide (INN, glibenclamide), and gemfibrozil, with the most pronounced effect being found for atorvastatin (inhibition constant, 0.7 +/- 0.4 micromol/L). Whereas simvastatin (lactone) itself was not transported by OATP2B1, atorvastatin was identified as a high-affinity substrate for OATP2B1 (Michaelis-Menten constant, 0.2 micromol/L) by direct transport measurement via liquid chromatography-tandem mass spectrometry., Conclusion: OATP2B1 is a high-affinity uptake transporter for atorvastatin and is expressed in the vascular endothelium of the human heart, suggesting its involvement in cardiac uptake of atorvastatin.

Background and Aims: Ezetimibe is an inhibitor of the cholesterol uptake transporter Niemann-Pick C1-like protein (NPC1L1). Target concentrations can be influenced by intestinal uridine diphosphate-glucuronosyltransferases (UGTs) and the efflux transporters P-glycoprotein (P-gp) (ABCB1) and multidrug resistance associated protein 2 (MRP2) (ABCC2). This study evaluates the contribution of these factors to the disposition and cholesterol-lowering effect of ezetimibe before and after induction of UGT1A1, P-gp, and MRP2 with rifampin (INN, rifampicin)., Methods: Serum concentrations of ezetimibe, as well as its glucuronide, and the plant sterols campesterol and sitosterol (surrogate for cholesterol absorption) were studied in 12 healthy subjects before and after rifampin comedication. In parallel, duodenal expression of UGT1A1, P-gp, MRP2, and NPC1L1 was quantified by use of real-time reverse transcriptase-polymerase chain reaction and quantitative immunohistochemical evaluation. The affinity of ezetimibe and its glucuronide to P-gp and MRP2 was assessed in P-gp- overexpressing Madin-Darby canine kidney II cells and P-gp-containing or MRP2-containing inside-out vesicles., Results: Up-regulation of intestinal P-gp, MRP2, and UGT1A1 (but not of NPC1L1) by rifampin was associated with markedly decreased areas under the curve of ezetimibe and its glucuronide (116 +/- 78.1 ng.h/mL versus 49.9 +/- 31.0 ng.h/mL and 635 +/- 302 ng.h/mL versus 225 +/- 86.4 ng.h/mL, respectively; both P = .002) and increased intestinal clearances (2400 +/- 1560 mL/min versus 5500 +/- 4610 mL/min [P = .003] and 76.6 +/- 113 mL/min versus 316 +/- 457 mL/min [P = .010], respectively) and nearly abolished sterol-lowering effects. Intestinal expression of UGT1A1, ABCB1, and ABCC2 was inversely correlated with the effects of ezetimibe on plant sterol serum concentrations. Parallel in vitro studies confirmed that ezetimibe glucuronide is a high-affinity substrate of MRP2 and has a low affinity to P-gp whereas ezetimibe interacts with P-gp and MRP2., Conclusions: The disposition and sterol-lowering effects of ezetimibe are modified by metabolic degradation of the drug via intestinal UGT1A1 and either intestinal or hepatic secretion (or both) via P-gp and MRP2.

Background: Gingival overgrowth is a common side effect of calcium antagonists. Although the pathogenesis is unknown, several lines of evidence point to a modulation of inflammatory processes. Because the calcium antagonists, albeit to a variable degree, act as inhibitors of P-glycoprotein (P-gp), the gene product of multidrug resistance 1 (MDR1), and inflammation may modify P-gp expression, we analyzed the MDR1 polymorphisms as risk factors for gingival overgrowth induced by calcium antagonists., Methods: Clinical, laboratory, and anamnestic data including periodontal parameters and use of calcium antagonists were assessed in a cross-sectional epidemiologic investigation (N = 1484). MDR1 polymorphisms in exon 21 G2677T/A and exon 26 C3435T were determined. P-gp expression was detected in gingival tissues. In a matched-pair analysis, 93 subjects using calcium antagonists and 186 not using them were compared., Results: P-gp is expressed in the endothelial layers of blood vessels obtained from healthy or inflamed gingiva. Subjects treated with calcium antagonists had significantly deeper gingival pockets than their drug-free counterparts (P <.0001). This drug-related side effect was associated with the MDR1 2677G/G or G/TA genotype (P <.001) but not with the variant genotype T/TA. This drug effect was proved by multiple regression analysis with adjustment for the risk factors of periodontitis (age, sex, smoking, and education) (P <.0001) and was associated with elevated C-reactive protein levels. The association of probing depth with the MDR1 polymorphism was confirmed in the matched-pair analysis (P <.0001)., Conclusion: Treatment with calcium antagonists leads to gingival hyperplasia, which is associated with the MDR1 G2677T/A polymorphism. The MDR1 genotype may modify the inflammatory response to the drugs.

Background and Methods: The antiepileptic drug carbamazepine is known to be an inducer of cytochrome P450 (CYP) 3A4 after binding to the nuclear pregnane X receptor. To evaluate whether it also regulates the multidrug transporter proteins P-glycoprotein (P-gp) and multidrug resistance protein MRP2 in humans, duodenal expression of multidrug resistance gene MDR1 messenger ribonucleic acid (mRNA) and MRP2 mRNA, content of P-gp and MRP2, and disposition of the nonmetabolized P-gp substrate talinolol after intravenous (30 mg) and long-term oral administration (100 mg for 19 days) were assessed in 7 healthy subjects (age, 23-35 years; body weight, 64-93 kg) before and after comedication of carbamazepine (600 mg for 14-18 days)., Results: Carbamazepine medication was associated with increased urinary excretion of D-glucaric acid and induction of carbamazepine elimination. Creatinine clearance was not affected. Duodenal expression of both MDR1 mRNA and MRP2 mRNA and the MPR2 protein was significantly induced, whereas the P-gp content was not affected. MDR1 mRNA expression and MPR2 mRNA expression were correlated ( r = 0.873, P <.001). After carbamazepine, metabolic clearance of intravenous talinolol was significantly increased. Residual clearance was significantly decreased in dependence on MDR1 mRNA expression ( r = -0.647, P =.012) and MRP2 mRNA expression ( r = -0.613, P =.020). Oral absorption of talinolol was significantly lower after carbamazepine comedication (53.2% +/- 15.5% versus 62.1% +/- 13.0%, P =.018), and renal clearance and metabolic clearance were significantly increased, correlated in each case with MDR1 mRNA ( r = 0.612, P =.020, and r = 0.554, P =.040, respectively) and MRP2 mRNA ( r = 0.596, P =.025, and r = 0.565, P =.035, respectively)., Conclusions: Aside from induction of CYP3A4, carbamazepine acts as an inducer of intestinal MDR1 mRNA, MRP2 mRNA, and MRP2 protein content.

Purpose: Hepatic venous occlusive disease is a severe side effect after administration of busulfan before hematopoietic stem cell transplantation. The syndrome is characterized by liver enlargement, fluid retention, jaundice, and weight gain. Endothelial injury has been described as the precipitating factor. The link between busulfan administration and endothelial damage has not been established thus far., Methods: Complementary deoxyribonucleic acid expression arrays were used to screen for busulfan responsive genes in ECV304 cells. Specific messenger ribonucleic acid and protein levels were examined by real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Serum samples of 15 pediatric patients with leukemia were analyzed for busulfan and cytokine levels., Results: We identified a member of the transforming growth factor beta superfamily, activin A, to be induced in the human cell line ECV304 after exposure to busulfan in a time- and concentration-dependent manner. Maximum effects were observed at 120 and 168 hours for activin A messenger ribonucleic acid and protein, respectively. Preincubation with the protein kinase C inhibitor bisindolylmaleimide I (10 nmol/L) abolished activin A induction by busulfan (P <.05). Activin receptors were detected in ECV304. Both tissue factor and cyclooxygenase 2 were significantly induced by busulfan (P <.05). In a parallel in vivo study a significant increase in serum activin A concentration was found 4.5 hours after the second dose of busulfan., Conclusion: The data demonstrate that busulfan induces activin A both in vitro and in vivo. In view of the multiple targets of activin A (inflammation, proliferation, apoptosis, and coagulation), these findings may be of relevance to our understanding of venous occlusive disease.

Background and Objectives: A single-nucleotide polymorphism (SNP) of the human multidrug-resistance gene in wobble position of exon 26 reportedly predicts expression and function of P-glycoprotein in human enterocytes and lymphocytes. Several other allelic variants of MDR1 have been identified, some of which lead to amino acid exchange with as yet unknown functional relevance., Methods: In healthy white volunteers, we investigated the influence of the hereditary variants C3435T in exon 26 and G2677T/A (Ala893Ser/Thr) in exon 21 and the influence of 7 frequent or putative functional SNPs on duodenal MDR1 messenger ribonucleic acid (n = 32) and immunoreactive P-glycoprotein (n = 37) expression. Moreover, the disposition of the probe drug talinolol was evaluated in 55 subjects after oral administration (100 mg) and in 23 subjects after intravenous administration(30 mg)., Results: Duodenal MDR1 messenger ribonucleic acid and P-glycoprotein, as assessed by real-time polymerase chain reaction (TaqMan) and immunostaining, were not influenced by any MDR1 polymorphism studied. Talinolol disposition was not affected by the exon 26 mutation C3435T. In carriers of the TT/TA variants of G2677T/A, the area under the serum concentration-time curve values of oral talinolol were slightly but significantly elevated compared with those in carriers of at least 1 wild-type allele (P <.05, Kruskal-Wallis test; P =.014, Mann-Whitney U test). However, multiple comparisons with combinations of putative functional SNPs did not confirm a significant influence of the MDR1 genotype on talinolol disposition., Conclusions: We did not identify any influence of MDR1 genotypes on duodenal expression of P-glycoprotein and disposition of talinolol in humans.