Etoposide and teniposide, the epipodophyllotoxins, stabilize the double stranded DNA cleavage normally catalyzed by topoisomerase II and inhibit faithful religation of DNA breaks (PMID: 1681541; 9748545). These double-strand DNA breaks subsequently trigger the desired antitumor effects of the drugs. Metabolism of etoposide is mediated by CYP3A4 and CPY3A5 (PMID: 8114683; 15319341), both of which are transcriptionally regulated by NR1I2 (i.e. Pregnane X receptor). Thus, xenobiotics that modulate NR1I2 activity (e.g. dexamethasone and rifampicin) have been observed to enhance etoposide clearance (PMID: 15578943; 12969965). In addition to CYP3A4/5 mediated reactions, conversion of etoposide to the O-demethylated metabolites (catechol and quinone) can also be catalyzed by prostaglandin synthases or myeloperoxidase (PMID: 3006680; 16841962; 11691792). These metabolites have similar potency at inhibiting topoisomerase II and are more oxidatively reactive than the parent drug (PMID: 11170441). Glutathione and glucuronide conjugation appear to inactivate parent drug and metabolite, and are mediated by GSTT1/GSTP1 and UGT1A1, respectively (PMID: 1315544; 3167829; 17151191; 12695346). Efflux of conjugated or unconjugated forms of etoposide has been associated with ABCC1, ABCC3 and ABCB1 (PMID: 8640791; 11581266), representing plausible mechanisms of drug resistance. Epipodophyllotoxins are highly effective anticancer agents, but can cause a delayed toxicity: treatment-related acute myeloid leukemia or myelodysplastic syndrome (t-ML) (PMID: 18509329; 1944468; 2822173). Drug-induced formation of MLL fusion genes has been associated with the development of t-ML (PMID: 8260707). Even though etoposide inhibits both topo II alpha and beta, the anti-tumor activity of etoposide is shown to be delivered primarily through inhibition of topo II alpha (PMID: 11531262) whilst the carcinogenic effect has been attributed to the beta isoform (PMID: 17578914). Recently, 64 genetic variants that contribute to etoposide-induced cytotoxicity were identified through a whole-genome association study (PMID: 17537913).
Yang Jun, Bogni Alessia, Schuetz Erin G, Ratain Mark, Dolan M Eileen, McLeod Howard, Gong Li, Thorn Caroline, Relling Mary V, Klein Teri E, Altman Russ B . "Etoposide pathway" Pharmacogenetics and genomics (2009).
Entities in the Pathway
Drugs/Drug Classes (3)
Relationships in the Pathway
|Arrow From||Arrow To||Controllers||PMID|
|catechol||quinone||MPO||11691792, 16841962, 2167725, 2854106, 2972290|
|CYP3A4||CYP3A4||NR1I2, VDR||10935643, 11723248, 11991950, 9145912|
|etoposide||catechol||CYP3A4, CYP3A5||2167725, 8114683|
|NR1I2||NR1I2||dexamethasone, etoposide, rifampin||12181418|
|quinone||glutathione conjugate||GSTP1, GSTT1||10900222, 1315544|
|TOP2A, TOP2B||TOP2A, TOP2B||catechol, etoposide, quinone||11531262, 17361331, 17578914, 2934259, 3030329, 3621161, 7979257, 9155056, 9748598|
|etoposide glucuronide||etoposide glucuronide||ABCC3||11581266|
|etoposide||etoposide||ABCB1, ABCC3||10426282, 11581266|
|glutathione conjugate||glutathione conjugate||ABCC1||7809167, 7915193, 7916458, 7954421, 8275468, 8640791, 9685354|
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|Impact of polymorphisms in drug pathway genes on disease-free survival in adults with acute myeloid leukemia. Journal of human genetics. 2013. Yee Sook Wah, Mefford Joel A, Singh Natasha, Percival Mary-Elizabeth, Stecula Adrian, Yang Kuo, Witte John S, Takahashi Atsushi, Kubo Michiaki, Matsuda Koichi, Giacomini Kathleen M, Andreadis Charalambos.|