Isotopically labeled chlorobenzenes as probes for the mechanism of cytochrome P-450 catalyzed aromatic hydroxylation
- National Heart, Lung and Blood Institute, Bethesda, MD (USA)
Noncompetitive and competitive intermolecular deuterium isotope effects were measured for the cytochrome P-450 catalyzed hydroxylation of a series of selectively deuterated chlorobenzenes. An isotope effect of 1.27 accompanied the meta hydroxylation of chlorobenzene-2H5 as determined by two totally independent methods (EC-LC and GC-MS assays). All isotope effects associated with the meta hydroxylation of chlorobenzenes-3,5-2H2 and -2,4,6-2H3 were approximately 1.1. In contrast, competitive isotope studies on the ortho and para hydroxylation of chlorobenzenes-4-2H1, -3,5-2H2, and -2,4,6-2H3 resulted in significant inverse isotope effects (approximately 0.95) when deuterium was substituted at the site of oxidation whereas no isotope effect was observed for the oxidation of protio sites. These results eliminate initial epoxide formation and initial electron abstraction (charge transfer) as viable mechanisms for the cytochrome P-450 catalyzed hydroxylation of chlorobenzene. The results, however, can be explained by a mechanism in which an active triplet-like oxygen atom adds to the pi system in a manner analogous to that for olefin oxidation. The resulting tetrahedral intermediate can then rearrange to phenol directly or via epoxide or ketone intermediates.
- OSTI ID:
- 6808260
- Journal Information:
- Biochemistry; (USA), Vol. 28:23; ISSN 0006-2960
- Country of Publication:
- United States
- Language:
- English
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59 BASIC BIOLOGICAL SCIENCES
CHLORINATED AROMATIC HYDROCARBONS
METABOLISM
DEUTERIUM
GAS CHROMATOGRAPHY
ISOTOPE EFFECTS
LIVER
MASS SPECTROSCOPY
MICROSOMES
MIXED-FUNCTION OXIDASES
MOLECULAR STRUCTURE
ORGANIC HALOGEN COMPOUNDS
RATS
TRACER TECHNIQUES
ANIMALS
AROMATICS
BODY
CELL CONSTITUENTS
CHROMATOGRAPHY
DIGESTIVE SYSTEM
ENZYMES
GLANDS
HALOGENATED AROMATIC HYDROCARBONS
HYDROGEN ISOTOPES
ISOTOPE APPLICATIONS
ISOTOPES
LIGHT NUCLEI
MAMMALS
NUCLEI
ODD-ODD NUCLEI
ORGANIC CHLORINE COMPOUNDS
ORGANIC COMPOUNDS
ORGANOIDS
ORGANS
OXIDOREDUCTASES
OXYGENASES
RIBOSOMES
RODENTS
SEPARATION PROCESSES
SPECTROSCOPY
STABLE ISOTOPES
VERTEBRATES
560300* - Chemicals Metabolism & Toxicology
550501 - Metabolism- Tracer Techniques