Oxidation of xenobiotics by recombinant human cytochrome P450 1B1

Tsutomu Shimada, Elizabeth M J Gillam, Thomas R. Sutter, Paul Timothy Strickland, F. Peter Guengerich, Hiroshi Yamazaki

Research output: Contribution to journalArticle

Abstract

Human cytochrome P450 (P450) 1B1 (CYP1B1) has recently been shown to be an important enzyme in the activation of diverse procarcinogens such as arylarenes, nitroarenes, and arylamines to reactive metabolites that cause DNA damage in the cells. However, it is not known whether this P450 enzyme also plays roles in the oxidation of certain drugs or model substrates commonly used in P450 assays. We examined the substrate oxidation activities of recombinant human CYP1B1 in yeast microsomes and compared these activities with those catalyzed by reconstituted systems containing recombinant CYP1A1 and CYP1A2 which were isolated from membranes of Escherichia coli in which respective cDNAs have been expressed. Catalytic activities towards some of the model substrates of other human P450 enzymes including CYP2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 were also determined and compared. CYP1B1 catalyzed benzo[a]pyrene 3-hydroxylation at rates lower than those of CYP1A1 but higher than those of CYP1A2. The activity towards 7-ethoxyresorufin O-deethylation catalyzed by CYP1B1 was about one-tenth of that of CYP1A1, but the K(m) values were lower for CYP1B1 than those for CYP1A1 and CYP1A2 CYP1B1 was also able to catalyze the oxidation of theophylline and caffeine, two prototypic substrates for CYP1A2. CYP1B1 did not oxidize other typical P450 substrates such as coumarin, tolbutamide, S-mephenytoin, chlorzoxazone, nifedipine, and testosterone, while low rates of oxidation of bufuralol and 7-ethoxycoumarin were found for CYP1B1. These results indicate that CYP1B1 has catalytic activities overlapping CYP1A1 and CYP1A2 with respect to the oxidation of drugs and model P450 substrates, although the relative catalytic roles in these three P450 enzymes differ depending upon the substrates examined. A distinct marker activity of CYP1B1 has not been identified.

Original languageEnglish (US)
Pages (from-to)617-622
Number of pages6
JournalDrug Metabolism and Disposition
Volume25
Issue number5
StatePublished - May 1997
Externally publishedYes

Fingerprint

Cytochrome P-450 CYP1A2
Cytochrome P-450 CYP1A1
Xenobiotics
Cytochrome P-450 Enzyme System
Oxidation
Substrates
Chlorzoxazone
Mephenytoin
Tolbutamide
Enzyme Activation
Catalyst activity
Benzo(a)pyrene
Hydroxylation
Nifedipine
Theophylline
Microsomes
Caffeine
Human Activities
Pharmaceutical Preparations
DNA Damage

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Shimada, T., Gillam, E. M. J., Sutter, T. R., Strickland, P. T., Guengerich, F. P., & Yamazaki, H. (1997). Oxidation of xenobiotics by recombinant human cytochrome P450 1B1. Drug Metabolism and Disposition, 25(5), 617-622.

Oxidation of xenobiotics by recombinant human cytochrome P450 1B1. / Shimada, Tsutomu; Gillam, Elizabeth M J; Sutter, Thomas R.; Strickland, Paul Timothy; Guengerich, F. Peter; Yamazaki, Hiroshi.

In: Drug Metabolism and Disposition, Vol. 25, No. 5, 05.1997, p. 617-622.

Research output: Contribution to journalArticle

Shimada, T, Gillam, EMJ, Sutter, TR, Strickland, PT, Guengerich, FP & Yamazaki, H 1997, 'Oxidation of xenobiotics by recombinant human cytochrome P450 1B1', Drug Metabolism and Disposition, vol. 25, no. 5, pp. 617-622.
Shimada T, Gillam EMJ, Sutter TR, Strickland PT, Guengerich FP, Yamazaki H. Oxidation of xenobiotics by recombinant human cytochrome P450 1B1. Drug Metabolism and Disposition. 1997 May;25(5):617-622.
Shimada, Tsutomu ; Gillam, Elizabeth M J ; Sutter, Thomas R. ; Strickland, Paul Timothy ; Guengerich, F. Peter ; Yamazaki, Hiroshi. / Oxidation of xenobiotics by recombinant human cytochrome P450 1B1. In: Drug Metabolism and Disposition. 1997 ; Vol. 25, No. 5. pp. 617-622.
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