Oxidation of 4-aryl- and 4-alkyl-substituted 2,6-dimethyl-3,5-bis(alkoxycarbonyl)-1,4-dihydropyridines by human liver microsomes and immunochemical evidence for the involvement of a form of cytochrome P-450

J Med Chem. 1986 Sep;29(9):1596-603. doi: 10.1021/jm00159a007.


4-Substituted 2,6-dimethyl-3,5-bis(alkoxycarbonyl)-1,4-dihydropyridines are important because of their roles as calcium channel blockers. The mixed-function oxidation of 14 4-aryl- and four 4-alkyl-substituted derivatives by human liver microsomes was examined. The major product of enzymatic oxidation of all the 4-aryl compounds was the pyridine derivative containing the 4-aryl group. The 4-alkyl compounds, in contrast, formed a pyridine derivative in which a hydrogen atom was present at the 4-position and the alkyl group was lost; these compounds also inactivated cytochrome P-450 and caused the loss of nifedipine oxidase activity after enzymatic oxidation. All of these reactions were extensively inhibited by an antibody raised to purified human liver nifedipine oxidase cytochrome P-450 (P-450NF), indicating a major role for this enzyme in the oxidation of these compounds. Oxidation of the 4-alkyl compounds led not only to the loss of P-450NF but also to decreases in catalytic activities of cytochrome P-450 isozymes catalyzing other reactions (phenacetin O-deethylation and hexobarbital 3'-hydroxylation). The results indicate that P-450NF (or closely related enzyme forms) is responsible for the oxidation of these nifedipine-related compounds in human liver microsomes and that metabolism is highly dependent upon 4-substitution; with alkyl substituents, radicals are postulated to leave P-450NF to attack other proteins.

Publication types

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

MeSH terms

  • Chemical Phenomena
  • Chemistry
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / metabolism*
  • Humans
  • Microsomes, Liver / enzymology*
  • NADP / pharmacology
  • Nifedipine / analogs & derivatives*
  • Nifedipine / metabolism
  • Oxidation-Reduction


  • Cytochrome P-450 Enzyme Inhibitors
  • NADP
  • Cytochrome P-450 Enzyme System
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • Nifedipine