Clear differences in the activity of both CYP3A4 and CYP3A5 were shown in the three major human races. Both 4beta-hydroxycholesterol and quinine/3-hydroxyquinine metabolic ratio showed a higher CYP3A activity in women than in men. The results give strong evidence that the plasma concentration of 4beta-hydroxycholesterol may be used as an endogenous marker of CYP3A activity (CYP3A4+5).

Cholesterol uptake and efflux are key metabolic processes associated with macrophage physiology and atherosclerosis. Peroxisome proliferator-activated receptor gamma (PPAR␥) and liver X receptor alpha (LXR␣) have been linked to the regulation of these processes. It remains to be identified how activation of these receptors is connected and regulated by endogenous lipid molecules. We identified CYP27, a p450 enzyme, as a link between retinoid, PPAR␥, and LXR signaling. We show that the human CYP27 gene is under coupled regulation by retinoids and ligands of PPARs via a PPAR-retinoic acid receptor response element in its promoter. Induction of the enzyme's expression results in an increased level of 27-hydroxycholesterol and upregulation of LXR-mediated processes. Upregulated CYP27 activity also leads to LXR-independent elimination of CYP27 metabolites as an alternative means of cholesterol efflux. Moreover, human macrophage-rich atherosclerotic lesions have an increased level of retinoid-, PPAR␥-, and LXR-regulated gene expression and also enhanced CYP27 levels. Our findings suggest that nuclear receptor-regulated CYP27 expression is likely to be a key integrator of retinoic acid receptor-PPAR␥-LXR signaling, relying on natural ligands and contributing to lipid metabolism in macrophages.Handling of lipids by macrophages is an important metabolic process in the context of hypercholesterolemia and the development of atherosclerotic lesions (20,32,44). For this reason it is critical to understand the regulatory processes associated with cholesterol and fatty acid uptake and release (efflux) in this cell type. A regulatory network has been associated with macrophage lipid metabolism in recent years. First, it has been shown that peroxisome proliferator-activated receptor gamma (PPAR␥), a member of the nuclear receptor superfamily, can be linked to macrophage maturation and uptake of modified (oxidized) low-density lipoprotein (LDL) (35,45). Later, the oxysterol receptor liver X receptor (LXR) was linked to macrophage lipid metabolism by showing that LXR␣ is a direct transcriptional target of PPAR␥ and could induce lipid transporters such as ABCA1 (9, 40) and ABCG1 (26). A coordinated lipid transport is likely to be regulated by these receptors. Linking of the two receptor systems (PPAR␥ and LXR␣) provides an attractive but not well understood pathway to explain lipid and cholesterol uptake and efflux from macrophages.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• CYP3A4 converts cholesterol into 4b-hydroxycholesterol.• We have suggested that 4b-hydroxycholesterol could be used as a clinical marker for CYP3A4 activity aiding in dose adjustments.• The kinetics of 4b-hydroxycholesterol formation is not known, however, and must be determined in order to establish under what conditions 4b-hydroxycholesterol can be used as a CYP3A marker. WHAT THIS STUDY ADDS• The concentration of 4b-hydroxycholesterol increases very slowly during CYP3A4/5 induction in paediatric patients.• Whereas induction of CYP3A4/5 was apparently complete within 1-2 weeks of carbamazepine treatment, plasma 4b-hydroxycholesterol levels continued to increase until at least 8 weeks of treatment. AIMSTo investigate the time course of the increase in 4b-hydroxycholesterol and carbamazepine plasma concentrations during treatment of paediatric patients with epilepsy. METHODSEight paediatric patients with newly diagnosed epilepsy were studied. Blood samples were drawn before and after about 1, 2, 4, 8 and 16 weeks of carbamazepine treatment. The plasma concentrations of 4b-hydroxycholesterol were determined by gas chromatography-mass spectrometry and carbamazepine and its epoxide metabolite by high-performance liquid chromatography. RESULTSThe basal plasma concentrations of 4b-hydroxycholesterol showed a large range of observed values between 18 and 99 ng ml . Plasma concentrations of carbamazepine and its epoxide metabolite reached steady state at 1-2 weeks after last dose change. CONCLUSIONSCarbamazepine treatment of paediatric patients with epilepsy resulted in an induction of CYP3A4/5 and a concomitant increase in plasma 4b-hydroxycholesterol. Whereas the induction of CYP3A4/5 was apparently complete after 1-2 weeks, the increase in 4b-hydroxycholesterol continued for several weeks. Thus CYP3A4 activity is not the only determinant of the circulating level of 4b-hydroxycholesterol. Additional factors such as transport and storage or presence of another enzyme may thus be of importance.

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Background Exhaustion disorder (ED) is a stress-induced disorder characterized by physical and mental symptoms of exhaustion that can be long-lasting. Although stress exposure is essential for the development of ED, little is known regarding the role of stressors in the maintenance of ED. The aim of the study was to investigate the role of work-related stressors, private-related stressors, and adverse childhood experiences in long-term recovery from ED. Methods A mixed methods design was used. The design was sequential, and data analysis was performed in two parts, where the first part consisted of qualitative analysis of patient records, and the second part consisted of statistical analysis of the data retrieved from the qualitative coding. Patient records from 150 patients with ED was analysed regarding work-related stressors, private-related stressors, and adverse childhood experiences. For each patient, two patient records were analysed, one from the time of diagnosis (baseline) and one from the follow-up clinical assessment, 7–12 years after diagnosis (follow-up). Out of the 150 patients, 51 individuals still fulfilled the diagnostic criteria for ED at follow-up (ED group) and 99 individuals no longer fulfilled the diagnostic criteria and were thus considered recovered (EDrec). Percentages in each group (ED and EDrec) reporting each stressor at baseline and follow-up were calculated as well as the differences in percentage points between the groups along with the 95% confidence intervals for the differences. Results At baseline, significantly more EDrec patients reported quantitative demands (73% EDrec, 53% ED) and managerial responsibilities (14% EDrec, 2% ED). Private-related stressors did not differ at baseline. At follow-up, significantly more ED patients reported managerial responsibilities (8 ED, 0% EDrec) and caregiver stress (child) (24% ED, 6% EDrec) and significantly more EDrec patients reported caregiver stress (parent) (6% EDrec, 0% ED). There were no differences regarding adverse childhood experiences. Conclusions The main conclusion is that neither adverse childhood experiences nor any of the stressors at baseline are associated with long-term ED. Ongoing stressors related to having responsibility for other people, such as managerial responsibilities or caring for a child with a chronic disease or psychiatric disorder, may be associated with long-term exhaustion.

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Background: Cognitive impairment occurs in 40%–70% of persons with multiple sclerosis (MS). Objective: To examine the effectiveness of natalizumab compared with other disease-modifying treatments (DMTs) on improving cognition as measured by the Symbol Digit Modalities Test (SDMT). Methods: Data were collected as part of Swedish nationwide phase IV surveillance studies (2007–2020). An increase in SDMT score by ⩾10% of the difference between maximum score possible (110) and the baseline value was defined as cognitive improvement. The likelihood of improvement was compared between natalizumab-treated individuals and individuals treated with other DMTs using mixed effect logistic regression. Trend in odds of improvement was investigated using slope analyses. Results: We included 2100 persons with relapsing-remitting MS treated with natalizumab and 2622 persons treated with other DMTs. At 6 months, 45% reached improvement. The natalizumab group showed largest odds of improvement during follow-up (odds ratio: 2.3, 95% confidence interval (CI): 1.5–3.5). The odds of improvement increased by 7% (95% CI: 6–7) per month of natalizumab treatment. The equivalent estimate was 4% (95% CI: 2–5) for other monoclonal antibodies and nonsignificant for oral or platform therapies. Conclusion: Treatment with natalizumab or other monoclonal antibodies is associated with a significantly faster likelihood of cognitive improvement than platform or oral DMTs.