These tools will no longer be maintained as of December 31, 2024. Archived website can be found here. PubMed4Hh GitHub repository can be found here. Contact NLM Customer Service if you have questions.


Pubmed for Handhelds

PUBMED FOR HANDHELDS

Search MEDLINE/PubMed

  • Title: Mechanistic studies on the cytochrome P450-catalyzed dehydrogenation of 3-methylindole.
    Author: Skiles GL, Yost GS.
    Journal: Chem Res Toxicol; 1996; 9(1):291-7. PubMed ID: 8924606.
    Abstract:
    The mechanism of 3-methyleneindolenine (3MEI) formation from 3-methylindole (3MI) in goat lung microsomes was examined using stable isotope techniques. 3MEI is highly electrophilic, and its production is a principal factor in the systemic pneumotoxicity of 3MI. Noncompetitive intermolecular isotope effects of DV = 3.3 and D(V/K) = 1.1 obtained after deuterium substitution at the 3-methyl position indicated either that hydrogen abstraction from the methyl group was not the initial rate-limiting step or that this step was rate-limiting and was masked by a high forward commitment and low reverse commitment to catalysis. An intramolecular isotope effect of 5.5 demonstrated that hydrogen atom abstraction was probably the initial oxidative and rate-limiting step of 3MI bioactivation or that deprotonation of an aminium cation radical, produced by one-electron oxidation of the indole nitrogen, was rate-limiting. However, a mechanism which requires deprotonation of the aminium cation radical is probably precluded by an unusual requirement for specific base catalysis at a site in the cytochrome P450 enzyme other than the heme iron. The pattern of 18O incorporation into indole-3-carbinol from 18O2 and H(2)18O indicated that approximately 80% of the indole-3-carbinol was formed in goat lung microsomes by hydration of 3MEI. However, the inverse reaction, dehydration of indole-3-carbinol, did not significantly contribute to the formation of 3MEI. These results show that 3MEI was formed in a cytochrome P450-catalyzed dehydrogenation reaction in which the rate-limiting step was presumably hydrogen atom abstraction from the 3-methyl position. The ratio of the amounts of 3MEI to indole-3-carbinol formed (50:1) indicated that dehydrogenation of 3MI is an unusually facile process when compared to the dehydrogenation of other substrates catalyzed by cytochrome P450 enzymes.
    [Abstract] [Full Text] [Related] [New Search]