Reversible and irreversible inhibition of CYP3A enzymes by tamoxifen and metabolites

Xue Jun Zhao, D. R. Jones, Ying Hong Wang, S. W. Grimm, S. D. Hall

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

1. Preliminary studies have identified cytochrome P450 (CYP) 3A4 and CYP1B1 as the human CYPs inhibited by tamoxifen. To quantify the inhibitory potency of tamoxifen and its major metabolites, the metabolism of three substrates of CYP3A, midazolam, diltiazem and testosterone, and 7-ethoxyresorufin as a substrate of CYP1B1 were examined in catalytic assays carried out using human liver microsomes and cDNA-expression systems. 2. Tamoxifen, N-desmethyltamoxifen, 4-hydroxytamoxifen and 3-hydroxytamoxifen reversibly inhibited midazolam 1′-hydroxylation, diltiazem N-demethylation and testosterone 6β-hydroxylation with Ki ranging from 3 to 37 μM in human liver microsomes. Tamoxifen, N-desmethyltamoxifen, 4-hydroxytamoxifen and 3-hydroxytamoxifen also reversibly inhibited the activity of cDNA-expressed CYP3A4, CYP3A5 and CYP1B1. 3. Tamoxifen and N-desmethyltamoxifen exhibited time-dependent inactivation of testosterone 6β-hydroxylation by cDNA-expressed CYP3A4 (+ cytochrome b5) yielding kinact and Ki of 0.04 min-1 and 0.2 μM for tamoxifen and 0.08 min-1 and 2.6 μM for N-desmethyltamoxifen. A metabolic intermediate complex (MIC) was also formed by tamoxifen and N-desmethyltamoxifen with CYP3A4 (+ cytochrome b5) and CYP3A4 but not with CYP3A5 or CYP3A7. Pre-incubation with 4-hydroxytamoxifen and 3-hydroxytamoxifen did not result in any CYP3A inactivation or detectable MIC formation. There was no detectable time-dependent inactivation or MIC formation with tamoxifen or metabolites with CYP1B1. 4. These data indicate that tamoxifen and its three major metabolites are effective inhibitors of CYP3A in vitro and that tamoxifen and N-desmethyltamoxifen are effective mechanism-based inhibitors. Thus, caution should be exercised when tamoxifen is coadministered with other CYP3A substrates.

Original languageEnglish
Pages (from-to)863-878
Number of pages16
JournalXenobiotica
Volume32
Issue number10
DOIs
StatePublished - Oct 1 2002

Fingerprint

Cytochrome P-450 CYP3A
Tamoxifen
Metabolites
Enzymes
Hydroxylation
Testosterone
Cytochromes b5
Diltiazem
Complementary DNA
Midazolam
Liver Microsomes
Liver
Substrates
Metabolism
N-desmethyltamoxifen
Assays

ASJC Scopus subject areas

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

Cite this

Zhao, X. J., Jones, D. R., Wang, Y. H., Grimm, S. W., & Hall, S. D. (2002). Reversible and irreversible inhibition of CYP3A enzymes by tamoxifen and metabolites. Xenobiotica, 32(10), 863-878. https://doi.org/10.1080/00498250210158230

Reversible and irreversible inhibition of CYP3A enzymes by tamoxifen and metabolites. / Zhao, Xue Jun; Jones, D. R.; Wang, Ying Hong; Grimm, S. W.; Hall, S. D.

In: Xenobiotica, Vol. 32, No. 10, 01.10.2002, p. 863-878.

Research output: Contribution to journalArticle

Zhao, XJ, Jones, DR, Wang, YH, Grimm, SW & Hall, SD 2002, 'Reversible and irreversible inhibition of CYP3A enzymes by tamoxifen and metabolites', Xenobiotica, vol. 32, no. 10, pp. 863-878. https://doi.org/10.1080/00498250210158230
Zhao, Xue Jun ; Jones, D. R. ; Wang, Ying Hong ; Grimm, S. W. ; Hall, S. D. / Reversible and irreversible inhibition of CYP3A enzymes by tamoxifen and metabolites. In: Xenobiotica. 2002 ; Vol. 32, No. 10. pp. 863-878.
@article{73065ceaadde46229d49e7889c443119,
title = "Reversible and irreversible inhibition of CYP3A enzymes by tamoxifen and metabolites",
abstract = "1. Preliminary studies have identified cytochrome P450 (CYP) 3A4 and CYP1B1 as the human CYPs inhibited by tamoxifen. To quantify the inhibitory potency of tamoxifen and its major metabolites, the metabolism of three substrates of CYP3A, midazolam, diltiazem and testosterone, and 7-ethoxyresorufin as a substrate of CYP1B1 were examined in catalytic assays carried out using human liver microsomes and cDNA-expression systems. 2. Tamoxifen, N-desmethyltamoxifen, 4-hydroxytamoxifen and 3-hydroxytamoxifen reversibly inhibited midazolam 1′-hydroxylation, diltiazem N-demethylation and testosterone 6β-hydroxylation with Ki ranging from 3 to 37 μM in human liver microsomes. Tamoxifen, N-desmethyltamoxifen, 4-hydroxytamoxifen and 3-hydroxytamoxifen also reversibly inhibited the activity of cDNA-expressed CYP3A4, CYP3A5 and CYP1B1. 3. Tamoxifen and N-desmethyltamoxifen exhibited time-dependent inactivation of testosterone 6β-hydroxylation by cDNA-expressed CYP3A4 (+ cytochrome b5) yielding kinact and Ki of 0.04 min-1 and 0.2 μM for tamoxifen and 0.08 min-1 and 2.6 μM for N-desmethyltamoxifen. A metabolic intermediate complex (MIC) was also formed by tamoxifen and N-desmethyltamoxifen with CYP3A4 (+ cytochrome b5) and CYP3A4 but not with CYP3A5 or CYP3A7. Pre-incubation with 4-hydroxytamoxifen and 3-hydroxytamoxifen did not result in any CYP3A inactivation or detectable MIC formation. There was no detectable time-dependent inactivation or MIC formation with tamoxifen or metabolites with CYP1B1. 4. These data indicate that tamoxifen and its three major metabolites are effective inhibitors of CYP3A in vitro and that tamoxifen and N-desmethyltamoxifen are effective mechanism-based inhibitors. Thus, caution should be exercised when tamoxifen is coadministered with other CYP3A substrates.",
author = "Zhao, {Xue Jun} and Jones, {D. R.} and Wang, {Ying Hong} and Grimm, {S. W.} and Hall, {S. D.}",
year = "2002",
month = "10",
day = "1",
doi = "10.1080/00498250210158230",
language = "English",
volume = "32",
pages = "863--878",
journal = "Xenobiotica",
issn = "0049-8254",
publisher = "Informa Healthcare",
number = "10",

}

TY - JOUR

T1 - Reversible and irreversible inhibition of CYP3A enzymes by tamoxifen and metabolites

AU - Zhao, Xue Jun

AU - Jones, D. R.

AU - Wang, Ying Hong

AU - Grimm, S. W.

AU - Hall, S. D.

PY - 2002/10/1

Y1 - 2002/10/1

N2 - 1. Preliminary studies have identified cytochrome P450 (CYP) 3A4 and CYP1B1 as the human CYPs inhibited by tamoxifen. To quantify the inhibitory potency of tamoxifen and its major metabolites, the metabolism of three substrates of CYP3A, midazolam, diltiazem and testosterone, and 7-ethoxyresorufin as a substrate of CYP1B1 were examined in catalytic assays carried out using human liver microsomes and cDNA-expression systems. 2. Tamoxifen, N-desmethyltamoxifen, 4-hydroxytamoxifen and 3-hydroxytamoxifen reversibly inhibited midazolam 1′-hydroxylation, diltiazem N-demethylation and testosterone 6β-hydroxylation with Ki ranging from 3 to 37 μM in human liver microsomes. Tamoxifen, N-desmethyltamoxifen, 4-hydroxytamoxifen and 3-hydroxytamoxifen also reversibly inhibited the activity of cDNA-expressed CYP3A4, CYP3A5 and CYP1B1. 3. Tamoxifen and N-desmethyltamoxifen exhibited time-dependent inactivation of testosterone 6β-hydroxylation by cDNA-expressed CYP3A4 (+ cytochrome b5) yielding kinact and Ki of 0.04 min-1 and 0.2 μM for tamoxifen and 0.08 min-1 and 2.6 μM for N-desmethyltamoxifen. A metabolic intermediate complex (MIC) was also formed by tamoxifen and N-desmethyltamoxifen with CYP3A4 (+ cytochrome b5) and CYP3A4 but not with CYP3A5 or CYP3A7. Pre-incubation with 4-hydroxytamoxifen and 3-hydroxytamoxifen did not result in any CYP3A inactivation or detectable MIC formation. There was no detectable time-dependent inactivation or MIC formation with tamoxifen or metabolites with CYP1B1. 4. These data indicate that tamoxifen and its three major metabolites are effective inhibitors of CYP3A in vitro and that tamoxifen and N-desmethyltamoxifen are effective mechanism-based inhibitors. Thus, caution should be exercised when tamoxifen is coadministered with other CYP3A substrates.

AB - 1. Preliminary studies have identified cytochrome P450 (CYP) 3A4 and CYP1B1 as the human CYPs inhibited by tamoxifen. To quantify the inhibitory potency of tamoxifen and its major metabolites, the metabolism of three substrates of CYP3A, midazolam, diltiazem and testosterone, and 7-ethoxyresorufin as a substrate of CYP1B1 were examined in catalytic assays carried out using human liver microsomes and cDNA-expression systems. 2. Tamoxifen, N-desmethyltamoxifen, 4-hydroxytamoxifen and 3-hydroxytamoxifen reversibly inhibited midazolam 1′-hydroxylation, diltiazem N-demethylation and testosterone 6β-hydroxylation with Ki ranging from 3 to 37 μM in human liver microsomes. Tamoxifen, N-desmethyltamoxifen, 4-hydroxytamoxifen and 3-hydroxytamoxifen also reversibly inhibited the activity of cDNA-expressed CYP3A4, CYP3A5 and CYP1B1. 3. Tamoxifen and N-desmethyltamoxifen exhibited time-dependent inactivation of testosterone 6β-hydroxylation by cDNA-expressed CYP3A4 (+ cytochrome b5) yielding kinact and Ki of 0.04 min-1 and 0.2 μM for tamoxifen and 0.08 min-1 and 2.6 μM for N-desmethyltamoxifen. A metabolic intermediate complex (MIC) was also formed by tamoxifen and N-desmethyltamoxifen with CYP3A4 (+ cytochrome b5) and CYP3A4 but not with CYP3A5 or CYP3A7. Pre-incubation with 4-hydroxytamoxifen and 3-hydroxytamoxifen did not result in any CYP3A inactivation or detectable MIC formation. There was no detectable time-dependent inactivation or MIC formation with tamoxifen or metabolites with CYP1B1. 4. These data indicate that tamoxifen and its three major metabolites are effective inhibitors of CYP3A in vitro and that tamoxifen and N-desmethyltamoxifen are effective mechanism-based inhibitors. Thus, caution should be exercised when tamoxifen is coadministered with other CYP3A substrates.

UR - http://www.scopus.com/inward/record.url?scp=0036793163&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036793163&partnerID=8YFLogxK

U2 - 10.1080/00498250210158230

DO - 10.1080/00498250210158230

M3 - Article

C2 - 12419016

AN - SCOPUS:0036793163

VL - 32

SP - 863

EP - 878

JO - Xenobiotica

JF - Xenobiotica

SN - 0049-8254

IS - 10

ER -