Krueger Sharon K, Vandyke Jonathan E, Williams David E, Hines Ronald N
Department of Environmental and Molecular Toxicology, The Linus Pauling Institute, Oregon State University, Corvallis, 97331, USA.
Drug Metab Rev. 2006;38(1-2):139-47. doi: 10.1080/03602530600569919.
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.
他莫昔芬被用于乳腺癌治疗及化学预防。他莫昔芬可能会增加患其他肿瘤的风险，尤其是子宫内膜癌。风险与益处的权衡取决于代谢激活与解毒的速率。细胞色素P450依赖的α-羟基化，随后进行磺化，代表一种代谢激活途径，产生能够与DNA共价结合的产物。相比之下，他莫昔芬N-氧化代表一种解毒途径，但需注意N-氧化物可还原回母体胺类。N-氧化途径将是本综述的重点。大卫·库普弗博士率先开展了关于细胞色素P450和含黄素单加氧酶（FMO）对他莫昔芬代谢的研究。我们与库普弗博士的实验室合作，最近确定了人肝微粒体中他莫昔芬N-氧化物产生水平较低的情况可能由FMO1与FMO3的动力学来解释。
