Mechanistic studies on the cytochrome P450-catalyzed dehydrogenation of 3-methylindole.
Chem Res Toxicol
; 9(1): 291-7, 1996.
Article
em En
| MEDLINE
| ID: mdl-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 (501) indicated that dehydrogenation of 3MI is an unusually facile process when compared to the dehydrogenation of other substrates catalyzed by cytochrome P450 enzymes.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Escatol
/
Sistema Enzimático do Citocromo P-450
Limite:
Animals
Idioma:
En
Revista:
Chem Res Toxicol
Assunto da revista:
TOXICOLOGIA
Ano de publicação:
1996
Tipo de documento:
Article
País de afiliação:
Estados Unidos