Elevated 4β‐hydroxycholesterol/cholesterol ratio in anorexia nervosa patients

Abstract

Recent studies have shown that the cytochrome P450 (CYP) 3A phenotype marker 4β‐hydroxycholesterol/cholesterol (4βOHC/C) ratio is negatively correlated with body weight in healthy volunteers, and that obese patients have lower 4βOHC levels than healthy controls. However, 4βOHC/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 4βOHC/C ratio. Furthermore, we wished to describe any association between body mass index (BMI) and 4βOHC/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 4βOHC/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). 4βOHC/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 4βOHC/C and BMI, which has previously been reported between 4βOHC/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.

Association between low body weight and cytochrome P‐450 enzyme activity in patients with anorexia nervosa

“…There was also a relatively weak correlation between BMI and CYP3A4 enzyme activity, with an r value of 0.44. Nevertheless, this is relatively close to the value of 0.56 found in the previous study using the 4β‐hydroxycholesterol/cholesterol ratio to estimate CYP3A4 activity 5 …”

“…This effect is principally the same as in another study in patients with anorexia nervosa, measuring the relationship between the endogenously produced CYP3A4 substrate cholesterol and its metabolite 4β‐hydroxycholesterol 5 . In that study the CYP3A4 activity was also higher in underweight patients with anorexia nervosa than in a group of healthy, normal‐weight controls 5 . In other studies, obese patients have had even lower CYP3A4 activities than normal‐weight controls 3,4,17 .…”

“…For CYP3A4, a seemingly paradoxical decreased CYP3A4 metabolic activity was observed with increasing body weight. This effect is principally the same as in another study in patients with anorexia nervosa, measuring the relationship between the endogenously produced CYP3A4 substrate cholesterol and its metabolite 4β‐hydroxycholesterol 5 . In that study the CYP3A4 activity was also higher in underweight patients with anorexia nervosa than in a group of healthy, normal‐weight controls 5 .…”

“…The only CYP enzyme for which some data exist in underweight subjects is CYP3A4. A preliminary study found that CYP3A4 enzyme activity was increased in patients with anorexia nervosa compared to a control group with normal weight, and that CYP3A4 activity was negatively correlated with body weight 5 . Also in healthy volunteers CYP3A4 activity decreases with increasing body weight 6 .…”

Phenotyping Cyp3a4/5 Using an Endogenous Biomarker in Children With Down Syndrome

“…In this context, the metabolite of cholesterol e.g. 4β-OHC reflects the activity of CYP3A4/5 so it was utilized as an endogenous biomarker for phenotyping of activity of these enzymes [14][15][16] . Studies deals with phenotyping Cytochrome P450 in DS are very limited.…”