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Systematic (IUPAC) name
Clinical data
AHFS/Drugs.com International Drug Names
MedlinePlus a684055
  • C
Pharmacokinetic data
Biological half-life 1.0 to 4.5 hours.
CAS Number 518-28-5 YesY
ATC code D06BB04
PubChem CID: 10607
DrugBank DB01179 N
ChemSpider 10162 YesY
UNII L36H50F353 YesY
KEGG D05529 YesY
ChEBI CHEBI:50305 YesY
Synonyms (5R,5aR,8aR,9R)-9-hydroxy-5-(3,4,5-trimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one
Chemical data
Formula C22H22O8
Molecular mass 414.405 g/mol
 N (what is this?)  (verify)

Podophyllotoxin (abbreviated as PPT), otherwise known as podofilox, is a non-alkaloid toxin lignan extracted from the roots and rhizomes of Podophyllum species.[1] Under the trade names Condylox, a gel, and Wartec, a solution or cream, it is used on the skin as a topical treatment of external genital warts, caused by some types of the human papillomavirus (HPV), and other warts. PPT and its synthetic derivatives display a wide selection in medical applications such as purgative, vesicant, antirheumatic, antiviral, and antitumor agents. These derivatives include etoposide, teniposide, and etopophos. Their anticancer activity has been heavily under study and used in various chemotherapies, including lung cancer, lymphomas, and genital tumors.

Historically, podophyllin, a resin extracted from Podophyllum species primarily comprising podophyllotoxin, was also used.

Natural abundance[edit]

It is present at concentrations of 0.3 to 1.0% by mass in the rhizome of American Mayapple (Podophyllum peltatum).[2][3] Another common source of podophyllotoxin is the rhizomes of Podophyllum hexandrum Royle (Berberidaceae).

It is biosynthesized from two molecules of coniferyl alcohol by phenolic oxidative coupling and a series of oxidations, reductions and methylations.[2]

Structural characteristic[edit]

The structure of podophyllotoxin was first elucidated in the 1930s.[4] Podophyllotoxin bears four consecutive chiral centers, labelled C-1 through C-4. The molecule also contains four almost planar fused rings. Four ends of podophyllotoxin have oxygen atoms at the functional groups dioxoles, methoxys, lactone, and secondary alcohol.[5]

Ring assignment and numbering of podophyllotoxin.

Derivatives of podophyllotoxin are synthesized as properties of the rings and carbon 1 through 4 are diversified. For example, ring A is not essential to antimitotic activity. Aromatization of ring C leads to loss of activity, possibly from ring E no longer being placed on the axial position. In addition, the stereochemistry at C-2 and C-3 configures a trans-lactone, which has more activity than the cis counterpart. Chirality at C-1 is also important as it implies an axial position for ring E.[5]


The biosynthetic route of podophyllotoxin was not completely eludicidated for many years; however in September 2015, the identity of the six missing enzymes in podophyllotoxin biosynthesis were reported for the first time.[6] Several prior studies have suggested a common pathway starting from coniferyl alcohol being converted to (+)-pinoresinol in the presence of a one-electron oxidant [7] through dimerization of stereospecific radical intermediate. Pinoresinol is subsequently reduced in the presence of co-factor NADPH to first lariciresinol, and ultimately secoisolariciresinol. Lactonization on secoisolariciresinol gives rise to matairesinol. Secoisolariciresinol is assumed to be converted to yatein through appropriate quinomethane intermediates,[7] leading to podophyllotoxin.

Proposed biosynthetic pathway leading to podophyllotoxin.

A sequence of enzymes involved has been reported to be dirigent protein (DIR), to convert coniferyl alcohol to (+)-pinocresol, which is converted by pinocresol-lariciresinol reductase (PLR) to (-)-secoisolariciresinol, which is converted by sericoisolariciresinol dehydrogenase (SDH) to (-)-matairesinol, which is converted by CYP719A23 to (-)-pluviatolide, which is likely converted by Phex13114 (OMT1) to (-)-yatein, which is converted by Phex30848 (2-ODD) to (-)-deoxypodophyllotoxin.[8] Though not proceeding through the last step of producing podophyllotoxin itself, a combination of six genes from the mayapple enabled production of the etoposide aglycone in tobacco plants.[8]

Toxicity and side effects[edit]

In toxic doses, podophyllotoxin causes intense enteritis, with all its characteristic symptoms, and severe CNS depression, which may end in death. The treatment is symptomatic, there being no specific antidote.

Even when the toxin is used topically, it can be systemically absorbed into the body, and fatal and near-fatal reactions have been reported, particularly when it is used extensively or on mucous membranes.[9] Neither podophyllin resin nor podofilox lotion or gel is used during pregnancy because these medications can be harmful to the fetus. The most common side effects near the application site are skin reactions, including burning, redness, pain, itching, swelling. There is some concern about the mutagenicity of some of the flavonoids in podophyllin.[10] Application can be immediately followed by burning or itching. Small sores, itching and peeling skin can also follow.[11]

Usages and applications[edit]

Podophyllotoxin displays a range of activities such as cathartic, purgative, antiviral, vesicant, and antihelminthic. Additionally, the lignan and its derivatives are exciting leads for anti-tumor agent. For instance, podophyllotoxin is the pharmacological precursor for the important anticancer drug etoposide.[7][12]

Podophyllin, a natural plant resin very high in podophyllotoxin content, has been used to remove genital warts since its efficacy was first demonstrated in 1942, although the reliability of this early report has been questioned.[10] This requires one application of podophyllin resin per week to the warts by a health professional, which is then washed off after 4 to 6 hours.[10] Petroleum jelly may be used to protect normal tissue near the warts from irritation. A health professional usually applies the resin once a week for at least 6 weeks or until warts disappear.[citation needed] It is unstable and therefore must be prepared shortly before use, which has possibly led to the lower efficacy shown in some clinical trials.[10]

Podophyllin is also used to treat molluscum contagiosum in the genital area.[medical citation needed] As the molluscum lesions can sometimes be quite numerous, scarring and hypopigmentation become an issue with cryosurgery.

Mechanism of action[edit]

Etoposide, a semisynthetic derivative of podophyllotoxin, induces DNA breakage through its inhibition of topoisomerase II. The drug is most active in the late S and early G2 phases of the cell cycle. Teniposide is an analog with very similar pharmacologic characteristics.[13]

Podophyllotoxin derivatives display binding activity to the enzyme topoisomerase II during the late S and early G2 stage. For instance, etoposide binds and stabilizes the temporary break caused by the enzyme, disrupts the reparation of the break through which the double-stranded DNA passes, and consequently stops DNA unwinding and replication.[2] Mutants resistant to either podophyllotoxin, or to its topoisomerase II inhibitory derivatives such as etoposide (VP-16), have been described in Chinese hamster cells.[14][15] The mutually exclusive cross-resistance patterns of these mutants provide a highly specific mean to distinguish the two kinds of podophyllotoxin derivatives.[15][16] Mutant Chinese hamster cells resistant to podophyllotoxin are affected in a protein P1 that was later identified as the mammalian HSP60 or chaperonin protein.[17][18]


Contraindications include diabetes mellitus, poor circulation, corticosteroid therapy, pregnancy, breast-feeding, and application to bleeding warts, moles, birthmarks, or unusual warts with hair growing from them.[19]


  1. ^ Xu, H; Lv, M; Tian,X (2009). "A review on hemisynthesis, biosynthesis, biological activities, mode of action, and structure-activity relationship of podophyllotoxins: 2003-2007.". Current Medicinal Chemistry 16 (3): 327–349. doi:10.2174/092986709787002682. PMID 19149581. 
  2. ^ a b c Canel, C; Moraes, RM; Dayan, FE; Ferreira, D (2000). "Molecules of Interest: Podophyllotoxin". Phytochemistry 54 (2): 115–120. doi:10.1016/s0031-9422(00)00094-7. 
  3. ^ J. L. Hartwell, A. W. Schrecker (1951). "Components of Podophyllin. V. The Constitution of Podophyllotoxin". Journal of the American Chemical Society 73 (6): 2909–2916. doi:10.1021/ja01150a143. 
  4. ^ Borsche, W.; Niemann J. (1932). "Über Podophyllin". Justus Liebigs Ann. Chem. 494: 126–142. doi:10.1002/jlac.19324940113. 
  5. ^ a b You, Y (2005). "Podophyllotoxin derivatives: current synthetic approaches for new anticancer agents.". Current Pharmaceutical Design 11 (13): 1695–1717. doi:10.2174/1381612053764724. PMID 15892669. 
  6. ^ Lau, W.; Satteley, E. (2015). "Six enzymes from mayapple that complete the biosynthetic pathway to the etoposide aglycone.". Science 349: 1224–1228. doi:10.1126/science.aac7202. 
  7. ^ a b c Gordaliza M, García PA, del Corral JM, Castro MA, Gómez-Zurita MA (2004). "Podophyllotoxin: distribution, sources, applications and new cytotoxic derivatives". Toxicon 44 (4): 441–59. doi:10.1016/j.toxicon.2004.05.008. PMID 15302526. 
  8. ^ a b Warren Lau and Elizabeth S. Sattely. "Six enzymes from the mayapple that complete the biosynthetic pathway to the etoposide aglycone". Sciene 349 (6253): 1224–1228. doi:10.1126/science.aac7202. 
  9. ^ von Krogh G, Longstaff E (December 2001). "Podophyllin office therapy against condyloma should be abandoned" (Registration required). Sex Transm Infect 77 (6): 409–12. doi:10.1136/sti.77.6.409. PMC 1744412. PMID 11714936. 
  10. ^ a b c d Longstaff E, von Krogh G (April 2001). "Condyloma eradication: self-therapy with 0.15-0.5% podophyllotoxin versus 20-25% podophyllin preparations--an integrated safety assessment". Regul. Toxicol. Pharmacol. 33 (2): 117–37. doi:10.1006/rtph.2000.1446. PMID 11350195. 
  11. ^ "PRODUCT INFORMATION WARTEC® SOLUTION" (PDF). GlaxoSmithKline Australia Pty Ltd. Retrieved 6 January 2013. 
  12. ^ Damayanthi Y, Lown JW (June 1998). "Podophyllotoxins: current status and recent developments". Curr. Med. Chem. 5 (3): 205–52. PMID 9562603. 
  13. ^ Anthony J. Trevor, Bertram G. Katzung, Marieke Kruidering-Hall, Susan B. Masters. Chapter 54: Cancer Chemotherapy. Katzung & Trevor's Pharmacology: Examination & Board Review, 10th edition.
  14. ^ Gupta, R.S.; Ho, T.K.W.; Moffat, M.R.K.; Gupta, R. (1982). "Podophyllotoxin-resistant mutants of Chinese hamster ovary cells. Alteration in a microtubule-associated protein". J. Biol. Chem. 257: 1071–1078. 
  15. ^ a b Gupta, R.S. (1983). "Genetic, biochemical and cross-resistance studies with mutants of Chinese hamster ovary cells resistant to the anticancer drugs VM-26 and VP16-213". Cancer Res 43: 1568–1574. 
  16. ^ Gupta, R.S. (1983). "Podophyllotoxin resistant mutants of Chinese hamster ovary cells: Cross resistance studies with various microtubule inhibitors and podophyllotoxin analogs". Cancer Res 43: 505–512. 
  17. ^ Picketts, D.J.; Mayanil, C.S.K.; Gupta, R.S. (1989). "Molecular cloning of a Chinese hamster mitochondrial protein related to the "chaperonin" family of bacterial and plant proteins". J. Biol. Chem. 264: 12001–12008. 
  18. ^ Jindal, S.; Dudani, A.K.; Singh, B.; Harley, C.B.; Gupta, R.S (1989). "Primary structure of a human mitochondrial protein homologous to the bacterial and plant chaperonins and to the 65 kDa mycobacterial antigen". Mol. Cell. Biol. 9: 2279–2283. doi:10.1128/mcb.9.5.2279. 
  19. ^ Podophyllum Resin, drugs.com

Further reading[edit]

  • Kelly M, Hartwell J. L. (1954). "The biological effects and the chemical composition of podophyllin: a review". Journal of the National Cancer Institute 14 (4): 967–1010. PMID 13233838. 
  • J. L. Hartwell, A. W. Schrecker (1951). "Components of Podophyllin. V. The Constitution of Podophyllotoxin". Journal of the American Chemical Society 73 (6): 2909–2916. doi:10.1021/ja01150a143.