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

Abstract

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 (T2DMobesity), 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. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?The current literature suggests that type 2 diabetes mellitus (T2DM) alters cytochrome P450 (CYP) activities in an iso-specific manner. However, an important limitation of previous studies investigating the impact of T2DM on CYP activities is that the close link between T2DM and obesity has not have been accounted for.

Initiation of glucose-lowering drugs reduces the anticoagulant effect of warfarin – but not through altered drug metabolism in patients with type 2 diabetes

“…Previous studies have focused on the drug-metabolizing activity (12–14) and the content of drug-metabolizing enzymes (14,27) in patients with type 2 diabetes compared to healthy individuals. In line with previous studies (12–14,28), our results suggest that the drug-metabolizing activity of CYP2C19 and CYP3A4 is decreased, and CYP1A2 activity is increased in patients with type 2 diabetes compared to healthy individuals (manuscript in the draft, ClinicalTrials . gov identifier NCT04840641) .…”

Initiation of glucose‐lowering drugs reduces the anticoagulant effect of warfarin—But not through altered drug metabolism in patients with type 2 diabetes

“…Previous studies have focused on the drug-metabolizing activity [13][14][15] and the content of drugmetabolizing enzymes 15,29 in patients with type 2 diabetes compared to healthy individuals. In line with previous studies, [13][14][15]30 our results suggest that the drug-metabolizing activity of CYP2C19 and CYP3A is decreased, and CYP1A2 activity is increased in patients with type 2 diabetes compared to healthy individuals (manuscript in the draft, ClinicalTrials.gov identifier NCT04840641). Further studies are needed to assess the mechanism behind this difference.…”

Clinically important alterations in pharmacogene expression in histologically severe nonalcoholic fatty liver disease

“…For certain CYP2C19 genotypes, reduced mRNA expression is the mechanism behind the altered clinical effect of drugs that are CYP2C19 substrates, providing further evidence 57 . Lastly, NAFLD was recently correlated with 60% lower omeprazole metabolism (a CYP2C19 substrate) 3 , and a 28% decrease in CYP2C19 protein 58 , which is broadly consistent with the expected effect of decreased CYP2C19 mRNA.…”