Substrate Specificity of Human Liver Cytochrome P-450 Debrisoquine 4-Hydroxylase Probed Using Immunochemical Inhibition and Chemical Modeling

Thomas Wolff, Linda M. Distlerath, Mark T. Worthington, Martha V. Martin, F. Peter Guengerich, John D. Groopman, George J. Hammons, Fred F. Kadlubar, Russell A. Prough, Thomas Wolff, Linda M. Distlerath

Research output: Contribution to journalArticlepeer-review

137 Scopus citations


A significant population of humans (5 to 10%) are phenotypic poor metaboiizers of debrisoquine. We have isolated the cytochrome P-450 isozyme from rat liver responsible for this activity and have shown that antibodies raised against the protein are able to inhibit this catalytic activity in human liver microsomes (Distlerath, L. M., and Guengerich, F. P., Proc. Natl. Acad. Sei. USA, 81: 7348-7352, 1984). These antibodies were utilized to determine which metabolic transformations are linked to debrisoquine 4-hydroxylation in human liver microsomes using techniques of immunochemical inhibition. The antibodies almost completely inhibited debrisoquine 4-hydroxylation and bufuralol 1 '-hydroxylation in microsomes prepared from several different human livers. The oxidation of the pyrrolidine alkaloids lasio-carpine and monocrotaline were inhibited by roughly one-third. The antibodies did not inhibit N, N-dimethylnitrosamine N-de-methylation, oxidation of vinylidene chloride to 2,2-chloroacetal-dehyde, oxidation of trichloroethylene to chloral, N-oxidation of azoprocarbazine, morphine N-demethylation, diazepam N-de-methylation, oxidation of benzo(a)pyrene to alkali-soluble metabolites, oxidation of benzo(a)pyrene 7,8-dihydrodiol to products covalently bound to DNA, the N- and ring-oxidation of 1- and 2-naphthylamine and 2-aminofluorene, or the conversion of afla-toxin Bi to DNA adduets or aflatoxin Qi. Studies with spacefilling models of the drugs the metabolism of which is associated with debrisoquine 4-hydroxylase in the literature indicated that all can be fitted to a general structure in which a basic nitrogen is about 5 Âaway from the site of carbon hydroxylation and a hydrophobic domain is near the site of hydroxylation. These results may be useful in predicting which chemicals may or may not be metabolized in an atypical manner by a segment of the human population.

Original languageEnglish (US)
Pages (from-to)2116-2122
Number of pages7
JournalCancer Research
Issue number5
StatePublished - May 1 1985
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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