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).
If you would like to reproduce this PharmGKB pathway diagram:
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.|