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4-Alkyl radical extrusion in the cytochrome P-450-catalyzed oxidation of 4-alkyl-1,4-dihydropyridines

Journal Article · · Biochemistry; (USA)
DOI:https://doi.org/10.1021/bi00420a020· OSTI ID:6948964
; ;  [1]
  1. Univ. of California, San Francisco (USA)
+ Show Author Affiliations

Rat liver microsomal cytochrome P-450 oxidizes the 4-methyl, 4-ethyl (DDEP), and 4-isopropyl derivatives of 3,5-bis(carbethoxy)-2,6-dimethyl-1,4,-dihydropyridine to mixtures of the corresponding 4-alkyl and 4-dealkyl pyridines. A fraction of the total microsomal enzyme is destroyed in the process. The 4-dealkyl to 4-alkyl pyridine metabolite ratio, the extent of cytochrome P-450 destruction, and the rate of spin-trapped radical accumulation are correlated in a linear inverse manner with the homolytic or heterolytic bond energies of the 4-alkyl groups of the 4-alkyl-1,4-dihydropyridines. No isotope effects are observed on the pyridine matabolite ratio, the destruction of cytochrome P-450, or the formation of ethyl radicals when (4-{sup 2}H)DDEP is used instead of DDEP. N-Methyl- and N-ethyl-DDEP undergo N-dealkylation rather than aromatization but N-phenyl-DDEP is oxidized to a mixture of the 4-ethyl and 4-deethyl N-phenylpyridinium metabolites. In contrast to the absence of an isotope effect in the oxidation of DDEP, the 4-deethyl to 4-ethyl N-phenylpyridinium metabolite ratio increases 6-fold when N-phenyl(4-{sup 2}H)DDEP is used. The results support the hypothesis that cytochrome P-450 catalyzes the oxidation of dihydropyridines to radical cations and show that the radical cations decay to nonradical products by multiple, substituent-dependent, mechanisms.

OSTI ID:
6948964
Journal Information:
Biochemistry; (USA), Journal Name: Biochemistry; (USA) Vol. 27:20; ISSN 0006-2960; ISSN BICHA
Country of Publication:
United States
Language:
English

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Related Subjects

550201* -- Biochemistry-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
ALKYLATION
ANIMALS
AZINES
BODY
CELL CONSTITUENTS
CHEMICAL REACTIONS
CHROMATOGRAPHY
CYTOCHROMES
DERIVATIZATION
DEUTERIUM COMPOUNDS
DIGESTIVE SYSTEM
ELECTRON SPIN RESONANCE
GLANDS
HETEROCYCLIC COMPOUNDS
HYDROGEN COMPOUNDS
LIQUID COLUMN CHROMATOGRAPHY
LIVER
MAGNETIC RESONANCE
MAMMALS
MICROSOMES
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANOIDS
ORGANS
OXIDATION
PIGMENTS
PROTEINS
PYRIDINES
RATS
RESONANCE
RIBOSOMES
RODENTS
SEPARATION PROCESSES
TIME DEPENDENCE
VERTEBRATES