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Cytochrome P-450 3A and 2D6 catalyze ortho hydroxylation of 4-hydroxytamoxifen and 3-hydroxytamoxifen (droloxifene) yielding tamoxifen catechol: involvement of catechols in covalent binding to hepatic proteins.
Drug Metab Dispos. 1999 Jun; 27(6):681-8.DM

Abstract

Earlier study suggested that 3,4-dihydroxytamoxifen (tam catechol), a tamoxifen metabolite, is proximate to the reactive intermediate that binds covalently to proteins and possibly to DNA (). The current study demonstrates that rat and human hepatic cytochrome P-450s (CYPs) catalyze tam catechol formation from tamoxifen (tam), 3-hydroxy-tam (Droloxifene), and 4-hydroxy-tam (4-OH-tam). Higher levels of catechol were formed from 4-OH-tam and 3-hydroxy-tam than from tam. Evidence that human hepatic CYP3A4 and 2D6 catalyze the formation of tam catechol from 4-OH-tam and supportive data that the catechol is proximate to the reactive intermediate, was obtained: 1) There was a good correlation (r = 0.82; p </=.0004) between steroidal 6beta-hydroxylase (CYP3A activity) and ortho hydroxylation of 4-OH-tam in human liver microsomes; 2) monospecific antibodies against CYP3A4 strongly inhibited catechol formation from 4-OH-tam and its covalent binding to proteins in human liver microsomes; 3) low levels of ketoconazole inhibited catechol tam accumulation and covalent binding of 4-OH-tam to human liver proteins; 4) among human P-450s expressed in insect cells (supersomes), only CYP3A4 and 2D6 noticeably catalyzed catechol formation, and cytochrome b5 markedly stimulated the CYP3A4 catalysis; and 5) human livers with high CYP3A and low or high CYP2D6 activity exhibited high catechol formation and those with low 3A and 2D6 activities formed only little catechol. These findings demonstrate that CYP3A4 and to a lesser extent 2D6 catalyze tam catechol formation and support the participation of tam catechol in covalent binding to proteins.

Authors+Show Affiliations

Worcester Foundation for Biomedical Research and Department of Pharmacology and Molecular Toxicology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

10348797

Citation

Dehal, S S., and D Kupfer. "Cytochrome P-450 3A and 2D6 Catalyze Ortho Hydroxylation of 4-hydroxytamoxifen and 3-hydroxytamoxifen (droloxifene) Yielding Tamoxifen Catechol: Involvement of Catechols in Covalent Binding to Hepatic Proteins." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 27, no. 6, 1999, pp. 681-8.
Dehal SS, Kupfer D. Cytochrome P-450 3A and 2D6 catalyze ortho hydroxylation of 4-hydroxytamoxifen and 3-hydroxytamoxifen (droloxifene) yielding tamoxifen catechol: involvement of catechols in covalent binding to hepatic proteins. Drug Metab Dispos. 1999;27(6):681-8.
Dehal, S. S., & Kupfer, D. (1999). Cytochrome P-450 3A and 2D6 catalyze ortho hydroxylation of 4-hydroxytamoxifen and 3-hydroxytamoxifen (droloxifene) yielding tamoxifen catechol: involvement of catechols in covalent binding to hepatic proteins. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 27(6), 681-8.
Dehal SS, Kupfer D. Cytochrome P-450 3A and 2D6 Catalyze Ortho Hydroxylation of 4-hydroxytamoxifen and 3-hydroxytamoxifen (droloxifene) Yielding Tamoxifen Catechol: Involvement of Catechols in Covalent Binding to Hepatic Proteins. Drug Metab Dispos. 1999;27(6):681-8. PubMed PMID: 10348797.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cytochrome P-450 3A and 2D6 catalyze ortho hydroxylation of 4-hydroxytamoxifen and 3-hydroxytamoxifen (droloxifene) yielding tamoxifen catechol: involvement of catechols in covalent binding to hepatic proteins. AU - Dehal,S S, AU - Kupfer,D, PY - 1999/5/29/pubmed PY - 1999/5/29/medline PY - 1999/5/29/entrez SP - 681 EP - 8 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 27 IS - 6 N2 - Earlier study suggested that 3,4-dihydroxytamoxifen (tam catechol), a tamoxifen metabolite, is proximate to the reactive intermediate that binds covalently to proteins and possibly to DNA (). The current study demonstrates that rat and human hepatic cytochrome P-450s (CYPs) catalyze tam catechol formation from tamoxifen (tam), 3-hydroxy-tam (Droloxifene), and 4-hydroxy-tam (4-OH-tam). Higher levels of catechol were formed from 4-OH-tam and 3-hydroxy-tam than from tam. Evidence that human hepatic CYP3A4 and 2D6 catalyze the formation of tam catechol from 4-OH-tam and supportive data that the catechol is proximate to the reactive intermediate, was obtained: 1) There was a good correlation (r = 0.82; p </=.0004) between steroidal 6beta-hydroxylase (CYP3A activity) and ortho hydroxylation of 4-OH-tam in human liver microsomes; 2) monospecific antibodies against CYP3A4 strongly inhibited catechol formation from 4-OH-tam and its covalent binding to proteins in human liver microsomes; 3) low levels of ketoconazole inhibited catechol tam accumulation and covalent binding of 4-OH-tam to human liver proteins; 4) among human P-450s expressed in insect cells (supersomes), only CYP3A4 and 2D6 noticeably catalyzed catechol formation, and cytochrome b5 markedly stimulated the CYP3A4 catalysis; and 5) human livers with high CYP3A and low or high CYP2D6 activity exhibited high catechol formation and those with low 3A and 2D6 activities formed only little catechol. These findings demonstrate that CYP3A4 and to a lesser extent 2D6 catalyze tam catechol formation and support the participation of tam catechol in covalent binding to proteins. SN - 0090-9556 UR - https://www.unboundmedicine.com/medline/citation/10348797/Cytochrome_P_450_3A_and_2D6_catalyze_ortho_hydroxylation_of_4_hydroxytamoxifen_and_3_hydroxytamoxifen__droloxifene__yielding_tamoxifen_catechol:_involvement_of_catechols_in_covalent_binding_to_hepatic_proteins_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&amp;pmid=10348797 DB - PRIME DP - Unbound Medicine ER -