Title

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

UMMS Affiliation

Worcester Foundation for Biomedical Research; Department of Pharmacology and Molecular Toxicology

Date

6-1-1999

Document Type

Article

Subjects

Animals; Biotransformation; Catechols; Cytochrome P-450 CYP2D6; Cytochrome P-450 Enzyme System; Estrogen Antagonists; Humans; Hydroxylation; Liver; Mixed Function Oxygenases; Pentobarbital; Protein Binding; Rats; Rats, Sprague-Dawley; Tamoxifen

Disciplines

Biochemistry, Biophysics, and Structural Biology | Life Sciences | Medicine and Health Sciences | Pharmacology, Toxicology and Environmental Health

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

Rights and Permissions

Citation: Drug Metab Dispos. 1999 Jun;27(6):681-8.

Related Resources

Link to Article in PubMed

Journal Title

Drug metabolism and disposition: the biological fate of chemicals

PubMed ID

10348797