| Autor: |
Jarman, Michael, Poon, Grace K., Rowlands, Martin G., Grimshaw, Rachel M., Horton, Martin N., Potter, Gerard A., McCague, Raymond |
| Zdroj: |
Carcinogenesis; 1995, Vol. 16 Issue 4, p683-688, 6p |
| Abstrakt: |
This study describes the application of on line HPLC—electrospray ionization MS in the structural determination of the metabolites formed following incubation with rat liver microsomes of an equimolar mixture of the anticancer drug tamoxifen and its [D-ethyl]-analogue. The ratio of 3:1 between unlabelled and D-labelled α-hydroxytamoxifen, indicating a large isotope effect for this metabolic process, accounted for the previously observed lower yield of DNA adducts formed in the livers of rats treated with D-tamoxifen compared with unlabelled drug. The loss of one deuterium atom on metabolism discriminated hydroxyethylated metabolites from others and enabled two further such metabolites to be detected, namely α-hydroxytamoxifen -oxide and α-hydroxy--desmethyltamoxifen of which the latter is novel. Furthermore, the use of [α-D-ethyl]- and [β-D-ethyl] tamoxifens discriminated α- from β-hydroxylated metabolites and proved that the metabolites described here were α-hydroxylated. In contrast to the α-hydroxylated metabolites, the other metabolites identified, namely tamoxifen -oxide, -desmethyltamoxifen, 4-hydroxytamoxifen and their deuterated counterparts were not depleted in the deuterated components. The use of on line HPLC—electrospray ionization MS combined with isotopic labelling is a powerful technique for probing the structures of metabolites, and, applied to tamoxifen, has provided further evidence that α-hydroxylation is an important pathway for the conversion of the drug into a DNA-reactive metabolite. [ABSTRACT FROM PUBLISHER] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
|
