Impact of type 2 diabetes on in vivo activities and protein expressions of cytochrome P450 in patients with obesity

• Published in: Clinical and translational science Vol. 15; no. 11; pp. 2685 - 2696
• Main Authors: Kvitne, Kine Eide, Åsberg, Anders, Johnson, Line K., Wegler, Christine, Hertel, Jens K., Artursson, Per, Karlsson, Cecilia, Andersson, Shalini, Sandbu, Rune, Skovlund, Eva, Christensen, Hege, Jansson‐Löfmark, Rasmus, Hjelmesæth, Jøran, Robertsen, Ida
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01-11-2022; John Wiley and Sons Inc; Wiley
• Subjects: Analysis; Basic Medicine; Bioavailability; Biopsy; Body composition; Body mass index; Caffeine; Care and treatment; Clinical Studies as Topic; Cross-Sectional Studies; CYP1A2 protein; Cytochrome; Cytochrome P-450; Cytochrome P-450 CYP1A2 - metabolism; Cytochrome P-450 CYP2C19 - genetics; Cytochrome P-450 CYP2C19 - metabolism; Cytochrome P-450 CYP2C9 - metabolism; Cytochrome P-450 CYP3A - metabolism; Cytochrome P-450 Enzyme System - metabolism; Cytochrome P450; Cytokines; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2; Drug Interactions; Drugs; Enzymes; Ethylenediaminetetraacetic acid; Humans; Laboratories; Medical research; Medicine, Experimental; Medicinska grundvetenskaper; Metabolism; Metabolites; Midazolam; Obesity; Omeprazole; Patients; Pharmacokinetics; Plasma; Proteins; Tumor necrosis factor-TNF; Type 2 diabetes; Urine; Weight control; Norway
• ISSN: 1752-8054; 1752-8062; 1752-8062
• DOI: 10.1111/cts.13394

Previous studies have not accounted for the close link between type 2 diabetes mellitus (T2DM) and obesity when investigating the impact of T2DM on cytochrome P450 (CYP) activities. The aim was to investigate the effect of T2DM on in vivo activities and protein expressions of CYP2C19, CYP3A, CYP1A2, and CYP2C9 in patients with obesity. A total of 99 patients from the COCKTAIL study (NCT02386917) were included in this cross‐sectional analysis; 29 with T2DM and obesity (T2DM‐obesity), 53 with obesity without T2DM (obesity), and 17 controls without T2DM and obesity (controls). CYP activities were assessed after the administration of a cocktail of probe drugs including omeprazole (CYP2C19), midazolam (CYP3A), caffeine (CYP1A2), and losartan (CYP2C9). Jejunal and liver biopsies were also obtained to determine protein concentrations of the respective CYPs. CYP2C19 activity and jejunal CYP2C19 concentration were 63% (−0.39 [95% CI: −0.82, −0.09]) and 40% (−0.09 fmol/μg protein [95% CI: −0.18, −0.003]) lower in T2DM‐obesity compared with the obesity group, respectively. By contrast, there were no differences in the in vivo activities and protein concentrations of CYP3A, CYP1A2, and CYP2C9. Multivariable regression analyses also indicated that T2DM was associated with interindividual variability in CYP2C19 activity, but not CYP3A, CYP1A2, and CYP2C9 activities. The findings indicate that T2DM has a significant downregulating impact on CYP2C19 activity, but not on CYP3A, CYP1A2, and CYP2C9 activities and protein concentrations in patients with obesity. Hence, the effect of T2DM seems to be isoform‐specific.