Etoposide Pathway

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).