RT Journal Article
SR Electronic
T1 Comprehensive Evaluation of Tamoxifen Sequential Biotransformation by the Human Cytochrome P450 System in Vitro: Prominent Roles for CYP3A and CYP2D6
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1062
OP 1075
DO 10.1124/jpet.104.065607
VO 310
IS 3
A1 Zeruesenay Desta
A1 Bryan A. Ward
A1 Nadia V. Soukhova
A1 David A. Flockhart
YR 2004
UL http://jpet.aspetjournals.org/content/310/3/1062.abstract
AB We performed comprehensive kinetic, inhibition, and correlation analyses in human liver microsomes and experiments in expressed human cytochromes P450 (P450s) to identify primary and secondary metabolic routes of tamoxifen (TAM) and the P450s catalyzing these reactions at therapeutically relevant concentrations. N-Desmethyl-TAM formation catalyzed by CYP3A4/5 was quantitatively the major primary metabolite of TAM; 4-hydroxy-TAM formation catalyzed by CYP2D6 (and other P450s) represents a minor route. Other minor primary metabolites include α -, 3-, and 4′-hydroxyTAM and one unidentified metabolite (M-I) and were primarily catalyzed by CYP3A4, CYP3A5, CYP2B6/2C19, and CYP3A4, respectively. TAM secondary metabolism was examined using N-desmethyl- and 4-hydroxy-TAM as intermediate substrates. N-Desmethyl-TAM was predominantly biotransformed to α-hydroxy N-desmethyl-, N-didesmethyl-, and 4-hydroxy N-desmethyl-TAM (endoxifen), whereas 4-hydroxy-TAM was converted to 3,4-dihydroxyTAM and endoxifen. Except for the biotransformation of N-desmethyl-TAM to endoxifen, which was exclusively catalyzed by CYP2D6, all other routes of N-desmethyl- and 4-hydroxy-TAM biotransformation were catalyzed predominantly by the CYP3A subfamily. TAM and its primary metabolites undergo extensive oxidation, principally by CYP3A and CYP2D6 to metabolites that exhibit a range of pharmacological effects. Variable activity of these P450s, brought about by genetic polymorphisms and drug interactions, may alter the balance of TAM effects in vivo. The American Society for Pharmacology and Experimental Therapeutics