Podophyllotoxin (PPT) is the active ingredient in Podofilox, which is a medical cream that is used to treat genital warts and molluscum contagiosum.[2] It is not recommended in HPV infections without external warts.[2] It can be applied either by a healthcare provider or the person themselves.[2]
Podophyllotoxin was first isolated in pure form in 1880 by Valerian Podwyssotzki (1818 – 28 January 1892), a Polish-Russian privatdozent at the University of Dorpat (now: Tartu, Estonia) and assistant at the Pharmacological Institute there.[6][7][8]
Podophyllotoxin possesses a large number of medical applications, as it is able to stop replication of both cellular and viral DNA by binding necessary enzymes. It can additionally destabilize microtubules and prevent cell division. Because of these interactions it is considered an antimitotic drug, although modern medicine instead use less orally toxic derivatives when such effect is wanted.[10]
Podophyllotoxin cream is commonly prescribed as a potent topical antiviral.[11] It is used for the treatment of HPV infections with external warts as well as molluscum contagisum infections.[11] 0.5% PPT cream is prescribed for twice daily applications for 3 days followed by 4 days with no application, this weekly cycle is repeated for 4 weeks.[12] It can also be prescribed as a gel, as opposed to cream. PPT is also sold under the names condyline and warticon.[13]
The most common side effects of podophyllotoxin cream are typically limited to irritation of tissue surrounding the application site, including burning, redness, pain, itching, swelling.[14] Application can be immediately followed by burning or itching. Small sores, itching and peeling skin can also follow, for these reasons it is recommended that application be done in a way that limits contact with surrounding, uninfected tissue[15]
Neither podophyllin resin nor podophyllotoxin lotions or gels are used during pregnancy because these medications have been shown to be embryotoxic in both mice and rats. Additionally, antimitotic agents are not typically recommended during pregnancy.[16] Additionally, it has not been determined if podophyllotoxin can pass into breast milk from topical applications and therefore it is not recommended for breastfeeding women.[17]
Podophyllotoxin destabilizes microtubules by binding tubulin and thus preventing cell division.[19][20] In contrast, some of its derivatives display binding activity to the enzyme topoisomerase II (Topo II) during the late S and early G2 stage. For instance, etoposide binds and stabilizes the temporary DNA 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.[21] Mutants resistant to either podophyllotoxin, or to its topoisomerase II inhibitory derivatives such as etoposide (VP-16), have been described in Chinese hamster cells.[22][23] The mutually exclusive cross-resistance patterns of these mutants provide a highly specific means to distinguish the two kinds of podophyllotoxin derivatives.[23][24] Mutant Chinese hamster cells resistant to podophyllotoxin are affected in a protein P1 that was later identified as the mammalian HSP60orchaperonin protein.[25][26][27]
Furthermore, podophyllotoxin is classified as an arytetralin lignan for[dubious – discuss] its ability to bind and deactivate DNA.[28] It and its derivates bind Topo II and prevent its ability to catalyze rejoining of DNA that has been broken for replication. Lastly, experimental evidence has shown that these arytetralin lignans can interact with cellular factors to create chemical DNA adducts, thus further deactivating DNA.[28]
The structure of podophyllotoxin was first elucidated in the 1930s.[29] Podophyllotoxin bears four consecutive chiral centers, labelled C-1 through C-4 in the following image. The molecule also contains four almost planar fused rings. The podophyllotoxin molecule includes a number of oxygen containing functional groups: an alcohol, a lactone, three methoxy groups, and an acetal.[30]
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.[30]
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.[31] Several prior studies have suggested a common pathway starting from coniferyl alcohol being converted to (+)-pinoresinol in the presence of a one-electron oxidant [10] 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,[10] leading to podophyllotoxin.
Podophyllotoxin has been successfully synthesized in a laboratory; however, synthesis mechanisms require many steps, resulting in a low overall yield. It therefore remains more efficient to obtain podophyllotoxin from natural sources.[32]
Podophyllotoxin and its derivatives are used as cathartic, purgative, antiviral agent, vesicant, antihelminthic, and antitumor agents. Podophyllotoxin derived antitumor agents include etoposide and teniposide.[10][37] These drugs have been successfully used in therapy against numerous cancers including testicular, breast, pancreatic, lung, stomach, and ovarian cancers.[32]
Podophyllotoxin is present at concentrations of 0.3% to 1.0% by mass in the rhizome of the American mayapple (Podophyllum peltatum).[21][39] Another common source is the rhizome of Sinopodophyllum hexandrum Royle (Berberidaceae).
^ abc"Podofilox". The American Society of Health-System Pharmacists. Retrieved 8 December 2016.
^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): 327–49. doi:10.2174/092986709787002682. PMID19149581.
^"Podophyllum Resin". The American Society of Health-System Pharmacists. Retrieved 8 December 2016.
Podwyssotzki V (1880). "Pharmakologische Studien über Podophyllum peltatum" [Pharmacological studies of Podophyllum peltatum]. Archiv für experimentelle Pathologie und Pharmakologie (in German). 13 (1–2): 29–52. doi:10.1007/BF01833268. S2CID33803976. Podwyssotzki named podophyllotoxin on p. 30: " … ich nenne sie bis auf weiteres Podophyllotoxin." ( … for the time being I call it "podophyllotoxin".)
^World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
^ abcdGordaliza M, García PA, del Corral JM, Castro MA, Gómez-Zurita MA (September 2004). "Podophyllotoxin: distribution, sources, applications and new cytotoxic derivatives". Toxicon. 44 (4): 441–59. doi:10.1016/j.toxicon.2004.05.008. PMID15302526.
^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". Regulatory Toxicology and Pharmacology. 33 (2): 117–37. doi:10.1006/rtph.2000.1446. PMID11350195.
^Moher LM, Maurer SA (August 1979). "Podophyllum toxicity: case report and literature review". The Journal of Family Practice. 9 (2): 237–40. PMID458391.
^Gordaliza M, Castro MA, del Corral JM, Feliciano AS (December 2000). "Antitumor properties of podophyllotoxin and related compounds". Current Pharmaceutical Design. 6 (18): 1811–1839. doi:10.2174/1381612003398582. PMID11102564.
^ abGupta RS (April 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 Research. 43 (4): 1568–1574. PMID6831403.
^Gupta RS (February 1983). "Podophyllotoxin-resistant mutants of Chinese hamster ovary cells: cross-resistance studies with various microtubule inhibitors and podophyllotoxin analogues". Cancer Research. 43 (2): 505–512. PMID6848174.
^ abYou Y (2005). "Podophyllotoxin derivatives: current synthetic approaches for new anticancer agents". Current Pharmaceutical Design. 11 (13): 1695–717. doi:10.2174/1381612053764724. PMID15892669.
^Kende AS, King ML, Curran DP (June 1981). "Total synthesis of (.+-.)-4'-demethyl-4-epipodophyllotoxin by insertion-cyclization". The Journal of Organic Chemistry. 46 (13): 2826–2828. doi:10.1021/jo00326a056.
^Macdonald DI, Durst T (August 1988). "A highly stereoselective synthesis of podophyllotoxin and analogues based on an intramolecular Diels-Alder reaction". The Journal of Organic Chemistry. 53 (16): 3663–3669. doi:10.1021/jo00251a003.
^Ziegler F, Schwartz JA (March 1978). "Synthetic studies on lignan lactones: aryl dithiane route to (.+-.)-podorhizol and (.+-.)-isopodophyllotoxone and approaches to the stegane skeleton". The Journal of Organic Chemistry. 43 (5): 985–991. doi:10.1021/jo00399a040.
^Klemm LH, Olson DR, White DV (December 1971). "Intramolecular Diels-Alder reactions. VII. Electroreduction of .alpha.,.beta.-unsaturated esters. I. Synthesis of rac-deoxypicropodophyllin by intramolecular Diels-Alder reaction plus trans addition of hydrogen". The Journal of Organic Chemistry. 36 (24): 3740–3743. doi:10.1021/jo00823a017.
Kelly M, Hartwell JL (February 1954). "The biological effects and the chemical composition of podophyllin: a review". Journal of the National Cancer Institute. 14 (4): 967–1010. PMID13233838.