Elevated 4ß-hydroxycholesterol/cholesterol ratio in anorexia nervosa patients.

Recent studies have shown that the cytochrome P450 (CYP) 3A phenotype marker 4ß-hydroxycholesterol/cholesterol (4ßOHC/C) ratio is negatively correlated with body weight in healthy volunteers, and that obese patients have lower 4ßOHC levels than healthy controls. However, 4ßOHC/C ratio in underweight patients has yet to be reported. The aim of this study was to examine potential differences in CYP3A activity between underweight patients with anorexia nervosa and normal-weight volunteers by measuring plasma 4ßOHC/C ratio. Furthermore, we wished to describe any association between body mass index (BMI) and 4ßOHC/C ratio in underweight patients. A total of 20 underweight patients and 16 normal-weight volunteers were included in the study, all females. Underweight patients had a median 4ßOHC/C ratio (molar ratio × 10-5) of 2.52 (range, 0.90-11.3) compared to 1.29 (0.56-2.09) in normal-weight subjects (Mann-Whitney P = 0.0005). 4ßOHC/C ratio was negatively correlated with BMI in underweight patients (r = -0.56, P = 0.011), and in the whole study population (r = -0.67, P < 0.0001). This suggests that the negative correlation between 4ßOHC/C and BMI, which has previously been reported between 4ßOHC/C and body weight in healthy volunteers, extends to underweight patients. The findings indicate that CYP3A activity increases with decreasing BMI, resulting in higher CYP3A activity in underweight patients compared to normal-weight subjects. The potential clinical relevance of this needs to be studied further by comparing pharmacokinetics of drugs subjected to CYP3A-mediated metabolism in underweight vs. normal-weight individuals.

Associations between Cytokine Levels and CYP3A4 Phenotype in Patients with Rheumatoid Arthritis.

Systemic inflammation has been linked to suppressed CYP3A4 activity. The aim of this study was to examine associations between levels of a broad selection of cytokines and CYP3A4 phenotype in patients with rheumatoid arthritis (RA). The study included 31 RA patients treated with tumor necrosis factor (TNF)-α inhibitors. CYP3A4 phenotype was measured as serum concentration of 4ß-hydroxycholesterol (4ßOHC) by ultra-performance liquid chromatography-tandem mass spectrometry in samples collected prior to and 3 months after initiation of treatment with TNF-α inhibitors. Serum levels of the following 21 cytokines were determined in the same samples using a bead-based multiplex immunoassay (Luminex technology): CCL2, CCL3, CXCL8, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, interferon γ, interleukin (IL)-1ß, IL-1 receptor antagonist (ra), IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12, IL-13, IL-15, IL-17A, IL-18, IL-23, and TNF-α Correlations between levels of cytokines and 4ßOHC were assessed by Spearman's rank correlation tests. Among the investigated cytokines, three were negatively correlated with CYP3A4 phenotype during treatment with TNF-α inhibitors: i.e., IL-1ra (r = -0.408, P = 0.023), IL-6 (r = -0.410, P = 0.022) and CXCL8 (r = -0.403, P = 0.025) (P ≥ 0.3 for all other cytokines). None of the analyzed cytokines were correlated with CYP3A4 phenotype prior to TNF-α inhibitor treatment (P > 0.1 for all cytokines). These findings suggest that immune responses associated with increased levels of IL-1ra, IL-6, and CXCL8 may suppress CYP3A4 metabolism. Further studies are required to evaluate these preliminary findings in different patient populations and also examine the possible molecular mechanisms behind our observations.