Flavin-containing monooxygenase activity can be inhibited by nitric oxide-mediated S-nitrosylation

Seung Duk Ryu, Hyeon Gyu Yi, Young Nam Cha, Ju Hee Kang, Ju Seop Kang, Yong Cheol Jeon, Hwon Kyum Park, Tae Moo Yu, Jung Nam Lee, Chang Shin Park

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29 Scopus citations

Abstract

Nitric oxide (NO) modifies the functions of a variety of proteins containing cysteine thiols or transition-metal centers, particularly by S-nitrosylation. In inflamed liver, NO is overproduced and hepatic drug-metabolizing enzymes, the flavin-containing monooxygenases (FMOs) and cytochrome P450s (CYPs), are suppressed. However, the NO-related mechanisms underlying the loss of these activities are not well understood, particularly for FMOs. In this study, we suggest that FMO3, the major FMO in human liver, is modified post-translationally by NO. This hypothesis is based on the imbalance observed between the decrease in FMO3 expression (40.7% of controls) and FMO3-specific ranitidine N-oxidation activity (15.1%), and on the partial or complete reversibility of FMO inhibition by sulfhydryl-reducing regents such as DTT (effective on both S-S and S-NO adducts) and ascorbate (effective on S-NO only). Furthermore, NO donors (SNP, SNAP, and Sin-1), including the pure NO donor DEA/NO, directly suppressed in vitro FMO activity (N- or S-oxidation of ranitidine, trimethylamine, and thiobenzamide) in human liver microsomal proteins and recombinant human FMO3. These activities were restored completely after treatment with DTT or ascorbate. These results suggest that NO-mediated S-nitrosylation is involved in the rigorous inhibition of FMO activity in vitro and in vivo, resulting in the suppression of FMO-based drug metabolism or detoxification.

Original languageEnglish
Pages (from-to)2559-2572
Number of pages14
JournalLife Sciences
Volume75
Issue number21
DOIs
StatePublished - 2004 Oct 8

Keywords

  • Ascorbate
  • Dithiothreitol
  • Flavin-containing monooxygenase
  • Nitric oxide
  • S-nitrosylation

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    Ryu, S. D., Yi, H. G., Cha, Y. N., Kang, J. H., Kang, J. S., Jeon, Y. C., Park, H. K., Yu, T. M., Lee, J. N., & Park, C. S. (2004). Flavin-containing monooxygenase activity can be inhibited by nitric oxide-mediated S-nitrosylation. Life Sciences, 75(21), 2559-2572. https://doi.org/10.1016/j.lfs.2004.05.018