ABSTRACT
We quantified the effect of acute ethanol exposure (initial blood concentrations 0.7 g/L) on major drug metabolizing enzymes and p-glycoprotein. Sixteen healthy Caucasians participated in a randomized crossover study with repeated administration of either vodka or water. Enzyme/transporter activity was assessed by a cocktail of probe substrates, including caffeine (CYP1A2/NAT2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), and digoxin (P-glycoprotein). The ratio of AUC0-t of dextromethorphan for ethanol/water coadministration was 1.95 (90% confidence interval (CI) 1.48-2.58). The effect was strongest in individuals with a CYP2D6 genotype predicting high activity (n = 7, ratio 2.66, 90% CI 1.65-4.27). Ethanol increased caffeine AUC0-t 1.38-fold (90% CI 1.25-1.52) and reduced intestinal midazolam extraction 0.77-fold (90% CI 0.69-0.86). The other probe drugs were not affected by ethanol. The results suggest that acute ethanol intake typically has no clinically important effect on the enzymes/transporters tested.
Subject(s)
Alcohol Drinking/metabolism , Cytochrome P-450 CYP1A2/metabolism , Cytochrome P-450 CYP2D6/metabolism , Cytochrome P-450 CYP3A/metabolism , Cytochrome P-450 Enzyme Inhibitors/administration & dosage , Ethanol/administration & dosage , Intestines/drug effects , Liver/drug effects , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Adult , Alcohol Drinking/adverse effects , Arylamine N-Acetyltransferase/metabolism , Cross-Over Studies , Cytochrome P-450 CYP1A2/genetics , Cytochrome P-450 CYP1A2 Inhibitors/administration & dosage , Cytochrome P-450 CYP2C19/metabolism , Cytochrome P-450 CYP2C9/metabolism , Cytochrome P-450 CYP2D6/genetics , Cytochrome P-450 CYP2D6 Inhibitors/administration & dosage , Cytochrome P-450 CYP3A/genetics , Cytochrome P-450 CYP3A Inhibitors/administration & dosage , Cytochrome P-450 Enzyme Inhibitors/adverse effects , Ethanol/adverse effects , Female , Genotype , Humans , Intestines/enzymology , Liver/enzymology , Male , Pharmacokinetics , Phenotype , Risk Assessment , Substrate Specificity , Young AdultABSTRACT
Traditionally, B cells have been best known for their role as producers of antibodies. However, in recent years, a growing body of evidence has accumulated showing that B cells fulfill a range of other immunologic functions. One of the functions that has attracted increasing attention is the capacity of B cells to induce antigen-specific activation of T cells through presentation of antigens. However, the analysis of this B cell function has been hampered by the lack of a phenotypically well-defined antigen-presenting B cell subset. Here, we report the identification of a human antigen-presenting B cell subset with strong immunostimulatory properties. This B cell subset is characterized by low expression of CD21 and high expression of the activation marker CD86 and exhibits strong T cell-stimulatory activity, as demonstrated by means of an autologous mixed-lymphocyte reaction. Phenotypically, CD21lowCD86pos immunostimulatory B cells (BAPC) represented CD27+ class-switched IgMnegIgDneg B lymphocytes and displayed a higher expression of cell surface receptors, which mediate the migration from peripheral blood to sites of inflammation. Flow cytometric analysis of peripheral blood obtained from individuals with inflammatory conditions revealed that the BAPC subset was expanded following vaccination and in patients with rheumatoid arthritis. Taken together, our work shows that BAPC represents a strongly immunostimulatory B cell subset, which could be a promising target for immunotherapeutic intervention in inflammatory diseases.
