Pathway Etoposide Pathway, Pharmacokinetics/Pharmacodynamics

Etoposide cellular disposition and effects.
Etoposide Pathway, Pharmacokinetics/Pharmacodynamics
mpo
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Description

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).

Authors: Jun Yang, Alessia Bogni, Erin G. Schuetz, Mark Ratain, M. Eileen Dolan, Howard McLeod, Caroline Thorn, Li Gong, Mary V. Relling.
Citation:
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).
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History:
Therapeutic Categories:
  • Anticancer agents

Entities in the Pathway

Genes (15)

Drugs/Drug Classes (3)

Relationships in the Pathway

Arrow FromArrow ToControllersPMID
ABCB1 ABCB1 NR1I2 11297522
catechol quinone MPO 11691792, 16841962, 2167725, 2854106, 2972290
CYP3A4 CYP3A4 NR1I2, VDR 10935643, 11723248, 11991950, 9145912
CYP3A5 CYP3A5 NR1I2
etoposide catechol CYP3A4, CYP3A5 2167725, 8114683
etoposide etoposide glucuronide UGT1A1 12695347
etoposide quinone PTGS1, PTGS2 3006680
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
vitamin D VDR
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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