Molecular & Cellular Toxicology

The Korean Society of Toxicogenomics and Toxicoproteomics (대한독성유전 단백체학회)
권호 표지

Enhanced Activity of Flavin-containing Monooxygenase in Human Subjects with High Body Mass Index and in Obese Mice Fed a High-fat Diet

  • Ko, Jeong-Hyeon (Department of Pharmacology and Medicinal Toxicology Research Center, Center for Advanced Medical Education, Inha University College of Medicine by BK-21 Project) ;
  • Lee, Tong-Joo (Department of Orthopedic Surgery, Inha University Hospital) ;
  • Park, Chang-Shin (Department of Pharmacology and Medicinal Toxicology Research Center, Center for Advanced Medical Education, Inha University College of Medicine by BK-21 Project) ;
  • Jang, Eun-Hee (Department of Pharmacology and Medicinal Toxicology Research Center, Center for Advanced Medical Education, Inha University College of Medicine by BK-21 Project) ;
  • Oh, Yun-Mi (Department of Pharmacology and Medicinal Toxicology Research Center, Center for Advanced Medical Education, Inha University College of Medicine by BK-21 Project) ;
  • Kang, Ju-Hee (Department of Pharmacology and Medicinal Toxicology Research Center, Center for Advanced Medical Education, Inha University College of Medicine by BK-21 Project)
  • Published : 2008.03.31
Download PDF
⟨ Previous Next ⟩

Abstract

The effect of obesity on the drug-metabolizing enzymes remains an important issue for clinician since obesity is a world wide epidemic problem. However, little is known about the effects of obesity on flavincontaining monooxygenase (FMO) production and activity. We show here for the first time that in vivo FMO activity determined by urinary ranitidine (RA) metabolites ratio in human, was higher in subjects with a high body mass index (BMI, kg/$m^2$, 21.97-30.32) than in those with an intermediate BMI (range 19.38-21.83). Moreover, there was a significant correlation between FMO activity and BMI in 209 subjects. In high fat diet-induced obese mice, we also observed that the hepatic expression of FMO (225% of lean mice) and the activity measured by the RA Noxidation rate ($513{\pm}58.1$ vs. $349{\pm}66.0$ pmol/hr per mg protein) were significantly higher than in lean mice fed a control diet. Unknown factors rather than leptin or insulin appeared to regulate the hepatic FMO production. Thus, FMO activity may be increased in obese or overweight individuals. Moreover, the regulation of FMO activity in subjects with morbid obesity, with or without complications and its clinical implications, should be investigated further.

Keywords

References

  1. Ziegler, D. M. A overview of the mechanism, substrate specificities, and structure of FMOs. Drug Metab Rev 34:503-511 (2002) https://doi.org/10.1081/DMR-120005650
  2. Borbas, T. et al. Insulin in flavin-containing monooxygenase regulation. Flavin-containing monooxygenase and cytochrome P450 activities in experimental diabetes. Eur J Pharm Sci 28:51-58 (2006) https://doi.org/10.1016/j.ejps.2005.12.011
  3. Cashman, J. R., Lattard, V. & Lin, J. Effect of total parenteral nutrition and choline on hepatic flavincontaining and cytochrome P-450 monooxygenase activity in rats. Drug Metab Dispos 32:222-229 (2004) https://doi.org/10.1124/dmd.32.2.222
  4. Coecke, S. et al. Hormonal regulation of microsomal flavin-containing monooxygenase activity by sex steroids and growth hormone in co-cultured adult male rat hepatocytes. Biochem Pharmacol 56:1047-1051 (1998) https://doi.org/10.1016/S0006-2952(98)00104-X
  5. Falls, J. G. et al. Regulation of mouse liver flavincontaining monooxygenases 1 and 3 by sex steroids. Arch Biochem Biophys 342:212-223 (1997) https://doi.org/10.1006/abbi.1997.9965
  6. Rouer, E. et al. Effects of genetic or chemically induced diabetes on imipramine metabolism. Respective involvement of flavin-containing monooxygenase and cytochrome P450-dependent monooxygenases. Drug Metab Dispos 15:524-528 (1987)
  7. Rouer, E., Rouet, P., Delpech, M. & Leroux, P. Purification and comparison of liver microsomal flavincontaining monooxygenase from normal and streptozotocin-diabetic rats. Biochem Pharmacol 37:3455-3459 (1988) https://doi.org/10.1016/0006-2952(88)90696-X
  8. WHO, Physical status: the use and interpretation of anthropometry. Report of a WHO Expert Consultation. WHO Technical Report Series Number 854 (1995)
  9. WHO, Obesity: preventing and managing the global epidemic. Report on a WHO Expert Consultation on Obesity. WHO/NUT/NCD/98.1. Technical Report Series Number 894 (2000)
  10. Kang, J . H. et al. Phentoypes of flavin-containing monooxygenase activity determined by ranitidine Noxidation are positively correlated with genotypes of linked FMO3 gene mutations in a Korean population. Pharmacogenetics 10:67-78 (2000) https://doi.org/10.1097/00008571-200002000-00009
  11. Chung, W. G. et al. Oxidation of ranitidine by isozymes of flavin-containing monooxygenase and cytochrome P450. Jpn J Pharmacol 84:213-220 (2000) https://doi.org/10.1254/jjp.84.213
  12. Deurenberg, P., Deurenberg-Yap, M. & Guricci, S. Asians are different from Caucasians and from each other in their body mass index/body fat per cent relationship. Obes Rev 3:141-146 (2002) https://doi.org/10.1046/j.1467-789X.2002.00065.x
  13. Wang, J. et al. Asians have lower body mass index (BMI) but higher percent body fat than do whites: comparisons of anthropometric measurements. Am J Clin Nutr 60:23-28 (1994) https://doi.org/10.1093/ajcn/60.1.23
  14. WHO expert consultation, Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet 363:157-163 (2004) https://doi.org/10.1016/S0140-6736(03)15268-3
  15. Brodfuehrer, J. I. & Zannoni, V. G. Modulation of the flavin-containing monooxygenase in guinea pigs by ascorbic acid and food restriction. J Nutr 117:286-290 (1987) https://doi.org/10.1093/jn/117.2.286
  16. Ryu, S. D. et al. Hepatic flavin-containing monooxygenase activity attenuated by cGMP-independent nitric oxide-mediated mRNA destabilization. Biochem Biophys Res Commun 324: 409-416 (2004) https://doi.org/10.1016/j.bbrc.2004.09.065