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Vol. 27, Issue 6, 681-688, June 1999
Worcester Foundation for Biomedical Research and Department of
Pharmacology and Molecular Toxicology, University of Massachusetts
Medical Center, Worcester, Massachusetts
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
(Dehal and Kupfer, 1996). 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 6
-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.
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