Regio- and stereoselective oxygenations by adult human liver flavin-containing monooxygenase 3. Comparison with forms 1 and 2

Chem Res Toxicol. Nov-Dec 1993;6(6):800-7. doi: 10.1021/tx00036a008.

Abstract

The cDNA for the adult human liver flavin-containing monooxygenase (form 3) (FMO3) was cloned, sequenced, and expressed in Escherichia coli. The cDNA-expressed FMO3 was used to investigate the regio- and stereoselective N- and S-oxygenation of a number of tertiary amines and sulfides, respectively. For comparison, the N- and S-oxygenation of the same chemicals and drugs were examined with adult human liver microsomes from a normal healthy female donor and FMO1 from pig liver and FMO2 from rabbit lung. Both cDNA-expressed FMO3 and adult human liver microsomes N-oxygenated trifluoperazine or 10-(N,N-dimethylaminoalkyl)-phenothiazines with similar substrate specificities. The substrate specificity for FMO3 differed, however, from that of pig liver FMO1. Nucleophilic sulfur-containing compounds [i.e., thiobenzamide, (4-bromophenyl)-1,3-oxathiolane, and 2-methyl-1,3-benzodithiole] were efficiently S-oxygenated by cDNA-expressed FMO3 and adult human liver microsomes. Stereoselective S-oxygenation of (+)- and (-)-(4-bromophenyl)-1,3-oxathiolane and 2-methyl-1,3-benzodithiole was therefore investigated. In general, the stereoselectivity observed for S-oxygenation in the presence of FMO3 was similar to that observed in the presence of adult human liver microsomes. In most cases examined, however, the stereoselectivity for S-oxygenation was quite distinct from that observed for pig liver FMO1. We conclude that FMO3 is the major form of FMO active in adult human liver. Because the stereoselectivity for X-oxygenation and the substrate specificity for tertiary amine N-oxygenation by cDNA-expressed FMO3 are distinct from those of pig liver FMO1, we conclude that the binding channel for each isoform is quite different.(ABSTRACT TRUNCATED AT 250 WORDS)

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Animals
  • DNA, Complementary / metabolism
  • Escherichia coli / genetics
  • Female
  • Gene Expression
  • Humans
  • Liver / enzymology*
  • Microsomes, Liver / enzymology
  • Oxygenases / chemistry*
  • Rabbits
  • Stereoisomerism
  • Substrate Specificity
  • Swine

Substances

  • DNA, Complementary
  • Oxygenases
  • dimethylaniline monooxygenase (N-oxide forming)