Effects of obesity on the flavin-containing monooxygenase and organic cation transporter 1 in human and laboratory animals

초록

BACKGROUND/AIMS &#8211; The effect of obesity on the drug-metabolizing enzymes or drug transporters remains an important issue for clinician since obesity is a world-wide epidemic problem. However, little is known about the effects of obesity on flavin-containing monooxygenase (FMO) and organic cation transporter 1 (OCT-1) expression and activity. Against these backgrounds, we evaluate whether obesity or increased body weight modulates the expression or activity of FMO and OCT-1 in human and laboratory animals. METHODS &#8211; We measured body mass index (BMI) and evaluated in vivo FMO activity determined by urinary ranitidine (RA) metabolites ratio in normal volunteers (n = 209) and their genotypes of FMO3. In high-fat (HF) diet-induced obese (DIO) or lean mice, we evaluated the hepatic expression and activity of FMO and OCT-1. RESUTS &#8211; The FMO activity was higher in subjects with a high body mass index (BMI, 21.97 &#8211; 30.32) than in those with an intermediate BMI (19.38 &#8211; 21.83). Moreover, there was a significant correlation between FMO activity and BMI in human. When we performed multiple regression analysis including demographic data and FMO3 genotypes, we found that genotype (P < 0.0001) and BMI (P = 0.031) were significant variables influencing FMO activity. Consistently, the hepatic expression (225% of lean mice) and activity of FMO (RA N-oxidation rate) were significantly higher than in lean mice. In addition, we observed that hepatic OCT-1 expression was higher in HF DIO mice compared with lean control. Using the OCT-1 substrate, metformin, we observed that the hepatic distribution of metformin was significantly higher in mice fed a HF diet. CONCLUSION &#8211; Our results suggest, at least in part, that obesity might have an effect on absorption, distribution and metabolism of substrate drugs for FMO or OCT-1 through an increase in hepatic expression of these proteins. Further studies on the regulation of hepatic expression of these pr