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Pawpaw

Scientific Name(s): Asimina triloba (L.) Dunal.
Common Name(s): Custard apple, Indiana banana, Kentucky banana, Pawpaw, Poor man's banana

Clinical Overview

Use

A. triloba has been used medicinally, as well as for food and as a material in fishing nets. Although it exhibits cytotoxic and pesticidal activity, published clinical trials are lacking to support its use for any indication.

Dosing

Clinical trials are lacking to provide guidance on dosing, and concerns of toxicity persist.

Contraindications

None identified; however, concerns of neurotoxicity persist.

Pregnancy/Lactation

Avoid use. Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

None well documented.

Adverse Reactions

May cause contact dermatitis.

Toxicology

Pawpaw fruit contains the neurotoxins annonacin and squamocin, and has been linked to Parkinsonism in some reports; however, case studies are lacking.

Botany

A. triloba, commonly known as "pawpaw," is from the custard-apple family and should not be confused with Carica papaya from the papaya family (see Papaya monograph).1, 2

A. triloba is a small, North American tree that grows approximately 3 to 12 meters tall. It is common in the temperate woodlands of the eastern United States and is an orchard crop in several states.3 Its large, drooping leaves give the plant a tropical appearance. The dark brown, velvety flowers, which can bloom for up to 6 weeks, are approximately 5 cm across and grow in umbrella-like whorls similar to those of some magnolia species. The fruit is smooth-skinned and yellow to greenish-brown in color, measures from approximately 8 to 15 cm long, and can reach up to 0.45 kg in weight. It resembles a short, thick banana and is similar in nutrient value but has a very short shelf life, which currently limits culinary and commercial uses.3 The yellow, soft, custard-like pulp is edible but sickly sweet in flavor and contains dark seeds.4, 5, 6

History

Pawpaw bark has been used medicinally due its useful alkaloid content. It has also been used as food by American Indians and the thin, fibrous, inner bark has been used to make fishing nets.4

The seeds of several Annonaceous species have an emetic properties, and in 1898 Eli Lilly Inc. sold an A. triloba extract for inducing emesis.6 Topical preparations exploit the pesticidal properties of the plant. An ointment for use in oral herpes is commercially available.7, 8

Chemistry

The bark, roots, twigs, and seeds of A. triloba contain acetogenins, long-chain, aliphatic compounds with 35 to 39 carbon atoms ending with a gamma-lactone, cyclized in tetrahydrofuran rings. Acetogenins are polyketide-derived molecules and are unique to the Annonaceae family. About 400 acetogenins from Asimina and other genera have been identified.7, 8, 9, 10, 11, 12, 13, 14

A variety of essential oils and other extracts from the leaf of the pawpaw plant have been described, with sesquiterpenes dominating the oil composition (83%).15, 16 The fruit, which contains phenolic acids and flavonoids, is a dietary source of antioxidants, although flavonoid content decreases greatly with ripening.3, 17, 18, 19 The fruit contains fatty acids ranging from C6 to C20.20

Uses and Pharmacology

Antimicrobial

Animal data

The pawpaw tree is usually insect- or disease-resistant because of its acetogenin content, which deters the feeding of many organisms.21 Antifungal and pesticidal properties have been demonstrated, with different plant parts having differing potencies. Small twigs yielded the most potent extract, while the leaves were the least potent. Unripe fruits, seeds, root wood and bark, and stem bark were also potent.22 Extracts of the plant were anthelminthic in vitro.23

Clinical data

Despite the availability of topical preparations, no clinical data exist regarding the use of A. triloba for antimicrobial effects.8

Cancer

Animal data

Certain acetogenins have exhibited cytotoxicity against human cancer cell lines.9, 24, 25, 26 A mechanism of action may be inhibition of mitochondrial nicotinamide adenine dinucleotide: ubiquinone oxidoreductase, causing a decrease in cellular adenosine triphosphate levels.21, 27 Acetogenins may also inhibit hypoxia-inducible factor-1, resulting in the suppression of angiogenesis in tumors.28 Despite concerns regarding the toxicity of A. triloba extracts, limited studies have been conducted in rodents. Acetogenins may be less toxic than standard chemotherapy.7

Clinical data

No clinical data exist regarding the use of A. triloba in cancer; however, a trial has been conducted using acetogenins from an unrelated plant.29

Dosing

Clinical trials are lacking to provide guidance on dosing, and concerns of toxicity persist.30

Pregnancy / Lactation

Avoid use. Information regarding safety and efficacy in pregnancy and lactation is lacking.

Interactions

None well documented.

Adverse Reactions

Handling of the fruit may produce a skin rash in sensitive individuals.1 The sensitizing potential of the pawpaw was examined in guinea pigs; the crude extract of the stem bark was found to be a weak sensitizer and to elicit allergic contact dermatitis. This report also determined the active compound asimicin to be a weak irritant.31 Acetogenins may also be irritating to the eyes.1

Toxicology

Pawpaw fruit contains the neurotoxins annonacin and squamocin,32 and has been linked to Parkinsonism in some reports;30 however, case studies are lacking.10 Neurotoxicity has been reported in rodents.8, 33 Ames tests for mutagenicity have largely been negative.8

References

1. Duke J, Bogenschutz-Godwin M, duCellier J, Duke P. Handbook of Medicinal Herbs. 2nd ed. Boca Raton, FL: CRC Press; 2002.
2. Asimina triloba L. USDA, NCRS. 2015. The PLANTS Database (http://plants.usda.gov/, 2015). National Plant Data Team, Greensboro, NC 27401-4901 USA. 2015.
3. Brannan RG, Peters T, Talcott ST. Phytochemical analysis of ten varieties of pawpaw (Asimina triloba [L.] Dunal) fruit pulp. Food Chem. 2015;168:656-661.25172760
4. Hocking GM. A Dictionary of Natural Products: Terms in the Field of Pharmacognosy Relating to Natural Medicinal and Pharmaceutical Materials and the Plants, Animals, and Minerals From Which They Are Derived. Medford, NJ: Plexus Publishing; 1997: 80.
5. Davidson A. Fruit: A Connoisseur's Guide and Cookbook. New York, NY: Simon & Schuster; 1991: 123-124.
6. Pomper KW. Acetogenin update. Kentucky State University. 2009. http://www.pawpaw.kysu.edu/PDF/AcetoUpdate3.pdf
7. Johnson HA, Oberlies NH, Alali FQ, McLaughlin JL. Thwarting resistance: Annonaceous acetogenins as new pesticidal and antitumor agents. In: Cutler SJ, Cutler HG, eds. Biologically Active Natural Products: Pharmaceuticals. Boca Raton, FL: CRC Press; 2000.
8. McLaughlin JL. Paw paw and cancer: annonaceous acetogenins from discovery to commercial products. J Nat Prod. 2008;71(7):1311-1321.18598079
9. Zhao GX, Rieser MJ, Hui YH, Miesbauer LR, Smith DL, McLaughlin JL. Biologically active acetogenins from stem bark of Asimina triloba. Phytochemistry. 1993;33(5):1065-1073.7764028
10. Gupta A, Pandey S, Shah DR, Yadav JS, Seth NR. Annonaceous acetogenins: The unrevealed area for cytotoxic and pesticidal activities. Syst Rev Pharm. 2011;2(2):104-109.
11. Kim EJ, Tian F, Woo MH. Asitrocin, (2,4)- cis- and trans-asitrocinones: novel bioactive mono-tetrahydrofuran acetogenins from Asimina triloba seeds. J Nat Prod. 2000;63(11):1503-1506.11087592
12. Kim EJ, Suh KM, Kim DH, et al. Asimitrin and 4-hydroxytrilobin, new bioactive annonaceous acetogenins from the seeds of Asimina triloba possessing a bis-tetrahydrofuran ring. J Nat Prod. 2005;68(2):194-197.15730242
13. Bruneton J. Pharmacognosy, Phytochemistry, Medicinal Plants. Paris, France: Lavoisier; 1995: 156.
14. Duke J. Handbook of Biologically Active Phytochemicals and Their Activities. Boca Raton, FL: CRC Press, Inc; 1992.
15. Derevinskaya T, et al. Some problems of the quality of drug-technical raw material of Asimina triloba. Farm Zh. 1983;38:49-52.
16. Farag MA. Chemical composition and biological activities of Asimina triloba leaf essential oil. Pharm Biol. 2009;47(10):982-986.
17. Brannan RG, Peters T, Talcott ST. Phytochemical analysis of ten varieties of pawpaw (Asimina triloba [L.] Dunal) fruit pulp. Food Chem. 2015;168:656-661.
18. Kobayashi H, Wang C, Pomper KW. Phenolic content and antioxidant capacity of pawpaw fruit (Asimina triloba L.) at different ripening stages. HortScience. 2008;43(1):268-270.
19. Harris GG, Brannan RG. A preliminary evaluation of antioxidant compounds, reducing potential, and radical scavenging of pawpaw (Asimina tribloba) fruit pulp from different stages of ripeness. LWT - Food Sci Technol. 2009;42(1):275-279.
20. Wood R, Peterson S. Lipids of the pawpaw fruit: Asimina triloba. Lipids. 1999;34(10):1099-1106.10580337
21. Janick J. Progress in New Crops. Arlington, VA: ASHS Press; 1996: 609-614.
22. Ratnayake S, Rupprecht JK, Potter VM, McLaughlin JL. Evaluation of various parts of the paw paw tree, Asimina triloba (Annonaceae), as commercial sources of the pesticidal annonaceous acetogenins. J Econ Entomol. 1992;85(6):2353-2356.1464691
23. Ferreira JF, Peaden P, Keiser J. In vitro trematocidal effects of crude alcoholic extracts of Artemisia annua, A. absinthium, Asimina triloba, and Fumaria officinalis: trematocidal plant alcoholic extracts. Parasitol Res. 2011;109(6):1585-1592.21562762
24. Zhao G, Hui Y, Rupprecht JK, McLaughlin JL, Wood KV. Additional bioactive compounds and trilobacin, a novel highly cytotoxic acetogenin, from the bark of Asimina triloba. J Nat Prod. 1992;55(3):347-356.1593281
25. He K, Shi G, Zhao GX, et al. Three new adjacent bis-tetrahydrofuran acetogenins with four hydroxyl groups from Asimina triloba. J Nat Prod. 1996;59(11):1029-1034.8946743
26. Woo MH, Cho KY, Zhang L, Gu ZM, McLaughlin JL. Asimilobin and cis- and trans-murisolinones, novel bioactive Annonaceous acetogenins from the seeds of Asimina triloba. J Nat Prod. 1995;58(10):1533-1542.8676130
27. Zhao GX, Miesbauer LR, Smith DL, McLaughlin JL. Asimin, asiminacin, and asiminecin: novel highly cytotoxic asimicin isomers from Asimina triloba. J Med Chem. 1994;37(13):1971-1976.8027979
28. Coothankandaswamy V, Liu Y, Mao SC, et al. The alternative medicine pawpaw and its acetogenin constituents suppress tumor angiogenesis via the HIF-1/VEGF pathway. J Nat Prod. 2010;73(5):956-961.20423107
29. Indrawati L; Indonesia University. Effect of Annona muricata leaves on colorectal cancer patients and colorectal cancer cells. In: ClinicalTrials.gov. Bethesda, MD: National Library of Medicine. https://clinicaltrials.gov/ct2/show/NCT02439580?term=NCT02439580&rank=1. NLM Identifier: NCT02439580. Updated May 12, 2015. Accessed September 7, 2015.
30. Levine RA, Richards KM, Tran K, Luo R, Thomas AL, Smith RE. Determination of neurotoxic acetogenins in pawpaw (Asimina triloba) fruit by LC-HRMS [published online January 22, 2015]. J Agric Food Chem.2559410410.1021/jf504500g
31. Smith RE, Tran K, Richards KM. Bioactive Annonaceous acetogenins. In: Rahman A, ed. Studies in Natural Products Chemistry. Vol 41. New York, NY: Elsevier; 2014:95-117.
32. Avalos J, Rupprecht JK, McLaughlin JL, Rodriguez E. Guinea pig maximization test of the bark extract from pawpaw, Asimina triloba (Annonaceae). Contact Dermatitis. 1993;29(1):33-35.8365150
33. Potts LF, Luzzio FA, Smith SC, Hetman M, Champy P, Litvan I. Annonacin in Asimina triloba fruit: implication for neurotoxicity. Neurotoxicology. 2012;33(1):53-58.22130466

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