Polymorphism of human cytochrome p-450

F. P. Guengerich, D. R. Umbenhauer, P. F. Churchill, P. H. Beaune, R. Böcker, R. G. Knodell, M. V. Martin, Robert (Stephen) Lloyd

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

1. The cytochrome P-450 forms involved in debrisoquine 4-hydroxylation (P-450DB), phenacetin O-deethylation (P-450PA), S-mephenytoin 4-hydroxylation (P-450MP), and nifedipine 1, 4-oxidation (P-450NF) have been purified to electrophoretic homogeneity from human liver microsomes. All of these reactions show in vivo polymorphism in humans. Evidence for the roles of the purified proteins in these processes comes from in vitro reconstitution and immunoinhibition studies. 2. The rat orthologs of these enzymes are as follows - P-450DB: P-450UT-H; P-450PA: P-450ISF-G; P-450MP: P-450UT-I; P-450NF; P-450NF: P-450PCN-E. Only in the case of P-450UT-H is the primary rat ortholog the same cytochrome P-450 which catalyses the catalytic reaction under consideration. 3. Reconstitution and immunochemical studies establish that the following reactions are catalysed by the individual P-450s - P-450DB: debrisoquine 4-hydroxylation, sparteine Δ5-oxidation, bufuralol 1'hydroxylation, encainide O-demethylation, and propanolol 4-hydroxylation; P-450PA: phenacetin O-deethylation; P-450MP: S-mephenytoin 4-hydroxylation and tolbutamide methyl hydroxylation; P-450NF: oxidation of nifedipine and 16 other substituted dihydropyridines, estradiol 2- and 4-hydroxylation, aldrin epoxidation, benzphetamine N-demethylation and 6hydroxylation of testosterone, androstenedione and cortisol. 4. A cDNA clone has been isolated that corresponds to rat P-450UT-H, as shown by a number of criteria. Studies with this probe establish that the sex and strain variation in debrisoquine 4-hydroxylase and related activities is related to differences in the levels of a 2-0 kb length mRNA present. The same probe also hybridizes to a human mRNA of the same size. 5. Polyclonal and monoclonal antibodies have been utilized to isolate several cDNA clones related to P-450NF from a bacteriophage λgt11 expression library; the largest of these is 2·3 kb in length. 6. Several cDNA clones related to P-450MP have also been isolated from a λgt11 library. One of these (2·5 kb) contains all of the coding sequence except for the last 14 nucleotides at the 5' end. The entire coding region has been sequenced; all unambiguously defined N-terminal amino acid residues of P-450MP are coded for by the nucleotide sequence.

Original languageEnglish (US)
Pages (from-to)311-316
Number of pages6
JournalXenobiotica
Volume17
Issue number3
DOIs
StatePublished - 1987
Externally publishedYes

Fingerprint

Hydroxylation
Cytochromes
Polymorphism
Mephenytoin
Nifedipine
Phenacetin
Oxidation
Debrisoquin
Rats
Complementary DNA
Clone Cells
Cytochrome P-450 Enzyme System
Encainide
Nucleotides
Benzphetamine
Sparteine
Aldrin
Dihydropyridines
Tolbutamide
Cytochrome P-450 CYP2D6

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology
  • Biochemistry
  • Health, Toxicology and Mutagenesis
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Guengerich, F. P., Umbenhauer, D. R., Churchill, P. F., Beaune, P. H., Böcker, R., Knodell, R. G., ... Lloyd, R. S. (1987). Polymorphism of human cytochrome p-450. Xenobiotica, 17(3), 311-316. https://doi.org/10.3109/00498258709043941

Polymorphism of human cytochrome p-450. / Guengerich, F. P.; Umbenhauer, D. R.; Churchill, P. F.; Beaune, P. H.; Böcker, R.; Knodell, R. G.; Martin, M. V.; Lloyd, Robert (Stephen).

In: Xenobiotica, Vol. 17, No. 3, 1987, p. 311-316.

Research output: Contribution to journalArticle

Guengerich, FP, Umbenhauer, DR, Churchill, PF, Beaune, PH, Böcker, R, Knodell, RG, Martin, MV & Lloyd, RS 1987, 'Polymorphism of human cytochrome p-450', Xenobiotica, vol. 17, no. 3, pp. 311-316. https://doi.org/10.3109/00498258709043941
Guengerich FP, Umbenhauer DR, Churchill PF, Beaune PH, Böcker R, Knodell RG et al. Polymorphism of human cytochrome p-450. Xenobiotica. 1987;17(3):311-316. https://doi.org/10.3109/00498258709043941
Guengerich, F. P. ; Umbenhauer, D. R. ; Churchill, P. F. ; Beaune, P. H. ; Böcker, R. ; Knodell, R. G. ; Martin, M. V. ; Lloyd, Robert (Stephen). / Polymorphism of human cytochrome p-450. In: Xenobiotica. 1987 ; Vol. 17, No. 3. pp. 311-316.
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