Oxidation of raloxifene to quinoids: potential toxic pathways via a diquinone methide and o-quinones.
Raloxifene was approved in 1997 by the FDA for the treatment of osteoporosis in postmenopausal women, and it is currently in clinical trials for the chemoprevention of breast cancer. Before widespread use as a chemopreventive agent in healthy women, the potential cytotoxic mechanisms of raloxifene should be investigated. In the current study, raloxifene was incubated with GSH and either rat or human liver microsomes, and the metabolites and GSH conjugates were characterized using liquid chromatography-tandem mass spectrometry. Raloxifene was converted to raloxifene diquinone methide GSH conjugates, raloxifene o-quinone GSH conjugates, and raloxifene catechols. For comparison, three raloxifene catechols were synthesized and characterized. In particular, 7-hydroxyraloxifene was found to oxidize to the 6,7-o-quinone. As compared with raloxifene diquinone methide, which has a half-life of less than 1 s in phosphate buffer, the half-life of raloxifene 6,7-o-quinone was much longer at t(1/2) = 69 +/- 2.5 min. The stability offered by raloxifene 6,7-o-quinone implies that it may be more toxic than raloxifene diquinone methide. Cytotoxicity studies in the human breast cancer cell lines S30 and MDA-MB-231 showed that 7-hydroxyraloxifene was more toxic than raloxifene in both cell lines. These results suggest that raloxifene could be metabolized to electrophilic and redox active quinoids, which have the potential to cause toxicity in vivo.
Yu
Linning
L
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, M/C 781, Chicago, Illinois 60612-7231, USA.
Liu
Hong
H
Li
Wenkui
W
Zhang
Fagen
F
Luckie
Connie
C
van Breemen
Richard B
RB
Thatcher
Gregory R J
GR
Bolton
Judy L
JL
D000818:Animals; D016227:Benzoquinones / Q000378:metabolism* / Q000633:toxicity; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D045563:Indolequinones / Q000032:analysis / Q000378:metabolism*; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D020849:Raloxifene Hydrochloride / Q000031:analogs & derivatives / Q000378:metabolism* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D020845:Selective Estrogen Receptor Modulators / Q000378:metabolism* / Q000633:toxicity
D016227:Benzoquinones; D045563:Indolequinones; D020845:Selective Estrogen Receptor Modulators; C068040:quinone methide; C004532:quinone; D020849:Raloxifene Hydrochloride; D005978:Glutathione