Selenoxidation by flavin-containing monooxygenases as a novel pathway for beta-elimination of selenocysteine Se-conjugates

M Rooseboom, J N Commandeur, G.C. Floor, A.E. Rettie, N P Vermeulen

Research output: Contribution to JournalArticleAcademicpeer-review


Previously, it was shown that beta-elimination of selenocysteine Se-conjugates by rat renal cytosol leading to pyruvate formation was not solely catalyzed by pyridoxal phosphate-dependent enzymes. It was hypothesized that selenoxidation of the selenocysteine Se-conjugates, followed by syn-elimination, may be an alternative mechanism for pyruvate formation. In this study, selenoxidation of selenocysteine Se-conjugates was studied using rat liver microsomes and recombinant human oxidative enzymes. For all six selenocysteine Se-conjugates that were tested, it was found that rat liver microsomal incubations led to the formation of pyruvate, whereas the corresponding selenoxides were not observed. Microsomal pyruvate formation from Se-benzyl-L-selenocysteine (SeBC) was NADPH-dependent, but only marginally inhibited by several P450 inhibitors. Inhibition by methimazole and by heat pretreatment and stimulation by n-octylamine indicated that flavin-containing monooxygenases are mainly responsible for pyruvate formation from the selenocysteine Se-conjugates in rat liver microsomes. In the case of S-benzyl-L-cysteine, the sulfur analogue of SeBC, pyruvate formation was not observed. For this substrate, a chemically stable sulfoxide could be observed, as previously described. By using recombinantly expressed human flavin-containing monooxygenases and P450 enzymes, it was delineated that SeBC is selenoxidized by human FMOs, but not by human P450s. The k(cat)/K(m) of selenoxidation was 3.8-fold higher for FMO-1 than for FMO-3. In conclusion, selenoxidation of selenocysteine Se-conjugates catalyzed by FMOs and subsequently syn-elimination has taken place as an alternative route for the formation of pyruvate from selenocysteine Se-conjugates. Although selenoxides are known to be easily reduced by thiol compounds, microsomal pyruvate formation from SeBC was only 75% inhibited in the presence of an excess of glutathione. This indicates that even in the presence of physiological concentrations of reducing thiol compounds, selenoxides of selenocysteine Se-conjugates may undergo syn-elimination to some extent. Whether selenoxides and/or selenenic acids that are formed are involved in the activity of chemopreventive selenocysteine Se-conjugates remains to be established.

Original languageEnglish
Pages (from-to)127-34
Number of pages8
JournalChemical Research in Toxicology
Issue number1
Publication statusPublished - Jan 2001


  • Animals
  • Cysteine
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System
  • Humans
  • Male
  • Microsomes, Liver
  • Oxidation-Reduction
  • Oxygenases
  • Pyruvic Acid
  • Rats
  • Rats, Wistar
  • Recombinant Proteins
  • Selenium Compounds
  • Selenium Oxides
  • Selenocysteine
  • Journal Article
  • Research Support, U.S. Gov't, P.H.S.


Dive into the research topics of 'Selenoxidation by flavin-containing monooxygenases as a novel pathway for beta-elimination of selenocysteine Se-conjugates'. Together they form a unique fingerprint.

Cite this