The role of flavin-containing monooxygenase (FMO) in the metabolism of tamoxifen and other tertiary amines.
Tamoxifen is utilized in breast cancer therapy and in chemoprevention. Tamoxifen may enhance risk for other neoplasias, especially endometrial cancer. The risk:benefit depends on the rate of metabolic activation versus detoxication. Cytochrome P450-dependent alpha-hydroxylation, followed by sulfonation, represents a metabolic activation pathway, producing products capable of covalent DNA adduction. In contrast, tamoxifen N-oxygenation represents a detoxication pathway, with the caveat that N-oxides can be reduced back to the parent amines. The N-oxygenation pathway will be the focus for this review. Dr. David Kupfer pioneered studies on cytochrome P450 and flavin-containing monooxygenase (FMO) tamoxifen metabolism. We collaborated with Dr. Kupfer's laboratory and recently determined that the low level of tamoxifen N-oxide production in human liver microsomes may be explained by the kinetics of FMO1 versus FMO3.
Krueger
Sharon K
SK
Department of Environmental and Molecular Toxicology, The Linus Pauling Institute, Oregon State University, Corvallis, 97331, USA.
Vandyke
Jonathan E
JE
Williams
David E
DE
Hines
Ronald N
RN