Abstract

The nonsteroidal antiestrogen tamoxifen (TAM) is subject to extensive biotransformation in humans and laboratory animals. In particular, the dimethylamino group of TAM undergoes N-demethylation and formal replacement with a hydroxyl group, affording major metabolites TAM amine and TAM alcohol, respectively. In the present study in ovariectomized rats, TAM was eliminated in part as metabolites arising from conversion of its basic side chain to an oxyacetic acid moiety. Thus, TAM acid (TA) was characterized spectrally from the urine of rats after intraperitoneal administration of TAM. TA was not detected in fecal extracts. In contrast, a second metabolite, 4-hydroxy TA (4HTA), was detected and characterized only from fecal extracts, indicative of a qualitative difference in routes of elimination for TA and 4HTA. Studies with rat liver fractions suggested TAM alcohol to be an intermediate metabolite in the conversion of TAM to TA and 4HTA. In liver microsomal fraction, TAM alcohol was converted to a novel metabolite, TAM aldehyde, which was isolated and characterized as its semicarbazone derivative. Coenzyme requirements for formation of this (derivative) metabolite, as well as for conversion of TA to 4HTA, indicated these transformations to be catalyzed by cytochromes P450. TAM aldehyde was shown to be a plausible intermediate in the formation of acidic metabolites by experiments that indicated oxidation of this to TA was catalyzed by aldehyde oxidase derived from liver cytosolic fraction.