Chapter 142 BUCKTHORN [ humboldtiana (J.A. Schultes) Zucc.]

BOTANICAL DESCRIPTION potential antineoplastic effects of a constituent (i.e., T - 514 toxin) of this . 1 The buckthorn family contains several genera of buck- thorn including Frangula, Karwinskia, , and PRINCIPAL TOXINS Sageretia .

Common Name: Coyotillo, Wild Cherry, Tullidora, Physicochemical Properties Buckthorn Scientifi c Name: Karwinskia humboldtiana (J.A. The fruit from K. humboldtiana contains at least four Schultes) Zucc. dimeric anthracenone neurotoxins identifi ed by their Botanical Family: (buckthorn) molecular weight (T - 496, T - 514, T - 516, T - 544). 2 The exact Physical Description: This spineless, woody or role of each compound in the production of neurotoxic- small reaches up to 1 –5 ft (∼ 30 – 150 cm) in ity is unclear. In animal models, the administration of height and has opposite, 1 – 3 in. (∼ 3 – 8 cm) long the green fruit produces liver, lung, and renal damage leaves on a stalk. Clusters of greenish fl owers with T - 514 being more cytotoxic than T - 544. 3 Experi- produce brownish black berries. mental animals given T - 544 develop classic ascending Distribution and Ecology: This shrub grows in semi- paralysis as well as somewhat less hepatic and pulmo- arid environments along canyons and gullies of nary damage than T - 514. Species of common buckthorn the southwestern United States, northern and ( Rhamnus spp.) also contain glycosides that are strong central Mexico, Central America, and northern cathartics. Colombia. The species of common buckthorn ( Rhamnus species) are ornamental hedges that Poisonous Parts have been naturalized in the eastern United States. Cascara buckthorn [Frangula purshiana (DC.) Cooper] is a small deciduous tree indigenous to All the plant parts are toxic, but the green fruit contains the Pacifi c Northwest. the highest concentration of neurotoxins. The amount of T- 544 neurotoxin varies with season and location. In EXPOSURE a series of seven fruit samples from different locations in Mexico, the T - 544 content of the fruits from K. hum- There are no specifi c medical indications for the use of boldtiana ranged from 0.69 – 1.6% (green fruit) and 0.4 – K. humboldtiana. In vitro studies have investigated the 1.26% (ripe fruit). 4

Medical Toxicology of Natural Substances, by Donald G. Barceloux, MD Copyright © 2008 John Wiley & Sons, Inc. 834 142 BUCKTHORN

Mechanism of Toxicity DIAGNOSTIC TESTING

In experimental animals, the administration of anthra- In case reports of chronic buckthorn intoxication, sural cenone neurotoxins from the fruit of K. humboldtiana nerve biopsy demonstrated distal segmental demyelin- for 2 – 3 weeks causes a progressive, ascending paralysis ation and axon degeneration with swelling of the similar to Guillain - Barr é syndrome. 5 However, the spe- Schwann cells due to phagocytosis of the myelin. 12,14 cifi c toxin has not been identifi ed. Observable effects Lymphocytic infi ltration does not usually occur. Animal during the fi rst week after administration of fruit from studies suggest the changes in the Schwann cells may be the buckthorn included lethargy, hypersensitivity to secondary to direct axon toxicity. 15 Motor conduction stimuli, and weight loss followed by a quiescent period. 6,7 velocities are reduced with an absence of conduction in An ascending paralysis developed by the second to the extremities in severe cases. Marked reduction in third week characterized by segmental demyelination of compound muscle action and fi brillation potentials large peripheral nerve fi bers, probably as a result of the consistent with axonal damage occurs rarely. 12 Analysis disruption of Schwann cell metabolism and axon trans- of cerebrospinal fl uid (CSF) does not demonstrate any port. 8 Animal studies also indicate that this fruit pro- abnormalities, and CSF protein and glucose concentra- duces acute nephrotoxicity characterized by marked tions are typically normal. reduction in renal perfusion pressure, hydropic degeneration of the proximal convoluted tubules, and TREATMENT increased sodium excretion in the urine. 9 In vitro studies suggest that oxidative stress mediated by reactive Treatment is supportive. Decontamination is intermediates may cause the cytotoxicity produced by unnecessary. T - 514. 10

DOSE RESPONSE References

The specifi c neurotoxin has not been identifi ed. 1. Peneyro - Lopez A , Martinez de Villarreal L , Gonzalez - Potentially toxic anthracenone compounds include Alanis R . In vitro selective toxicity of toxin T - 514 T - 514 (peroxisomicine A1), T - 516, T - 544, and T - 496. 11 from Karwinskia humboldtiana (buckthorn) plant on The amount of buckthorn fruit necessary to produce various human tumor cell lines . Toxicology 1994 ; 92 : 217 – 227 . neurotoxicity is not well defi ned. 2. Dreyer D , Arai I , Bashuman C , Anderson W , Smith R , Daves D . Toxins causing non- infl ammatory paralytic neu- TOXICOKINETICS ropathy. Isolation and structure elucidation. J Am Chem Soc 1975 ; 97 : 4986 – 4990 . There are few data on the toxicokinetics of suspected 3. Bermudez MV , Gonzalez - Spencer D , Guerrero M , toxins (T - 496, T - 514, T - 516, T - 544) in buckthorn. Waksman N , Pineyro A . Experimental intoxication with fruit and purifi ed toxins of buckthorn (Karwinskia hum- CLINICAL RESPONSE boldtiana ) . Toxicon 1986 ; 24 : 1091 – 1097 . 4. Guerrero M , Pineyro A , Waksman N . Extraction and quantifi cation of toxins from Karwinskia humboldtiana Case reports indicate that chronic consumption of (tullidora) . Toxicon 1987 ; 25 : 565 – 568 . K. humboldtiana causes a progressive, symmetrical 5. Bermudez MV , Mart í nez FJ , Salazar ME , Waksman N , polyneuropathy characterized by a fl accid quadriplegia 12 Pieyro A . Experimental acute intoxication with ripe fruit without sensory changes. Deep tendon refl exes are of Karwinskia humboldtiana in rat, guinea - pig, hamster usually absent, and cranial nerve signs are normal. and dog . Toxicon 1992 ; 30 : 1493 – 1496 . Occasionally, respiratory insuffi ciency and pneumonia 13 6. Mu ñ oz - Mart í nez EJ , Cueva J , Joseph - Nathan P . Denerva- complicate the ascending neuropathy. The onset of tion caused by tullidora (Karwinskia humboldtiana ) . paralysis ranges between about 1 – 6 weeks after inges- Neuropathol Appl Neurobiol 1983 ; 9 : 121 – 134 . 14 tion of the fruit. A slow, gradual recovery usually 7. Mitchell J , Weller RO , Evans H , Arai I , Daves GD Jr . occurs, although some refl ex defi cits may remain. Expo- Buckthorn neuropathy. Effects of intraneural injection of sure to other Rhamnus species may cause diarrhea, but Karwinskia humboldtiana toxins . Neuropathol Appl Neu- neurological abnormalities occur only following expo- robiol 1978 ; 4 : 85 – 97 . sure to K. humboldtiana. The differential diagnosis of 8. Mu ñ oz - Mart í nez EJ , Cu é llar - Pedroza LH , Rubio - Franchini chronic buckthorn neuropathy includes Guillain - Barr é C , J á uregui - Ric ó n J , Joseph - Nathan P . Depression of fast syndrome and poliomyelitis. axonal transport in axons demyelinated by intraneural 835 PART 4 TOXIC

injection of a neurotoxin from K. humboldtiana . Neuro- 12. Mart í nez HR , Bermudez MV , Rangel - Guerra RA , chem Res 1994 ; 19 : 1341 – 1348 . De Leon Flores L . Clinical diagnosis in Karwinskia 9. Jaramillo - Juarez F , Ortiz GG , Rodriguez - Vazquez ML , humboldtiana polyneuropathy . J Neurol Sci 1998 ; 154 : Falcon - Franco MA , Feria - Velasco A . Renal failure during 49 – 54 . acute toxicity produced by tullidora ingestion ( Karwinskia 13. Calderon - Gonzalez R , Rizzi - Hernandez H . Buckthorn humboldtiana ) . Gen Pharmacol 1995 ; 26 : 649 – 653 . polyneuropathy . N Engl J Med 1967 ; 277 : 69 – 71 . 10. Garza - Ocanas L , Zanatta - Calderon MT , Acosta D , Torres - Alanis O , Pineyro - Lopez A . Production of reactive oxygen 14. Ocampo - Roosens LV , Ontiveros - Nevares PG , Fernandez - species by toxin T- 514 of genus Karwinskia in vitro . Toxicol Lucio O . Intoxication with buckthorn ( Karwinskia hum- In Vitro 2003 ; 17 : 19 – 25 . boldtiana ): report of three siblings . Pediatr Dev Pathol 2007 ; 10 : 66 – 68 . 11. Salazar - Leal ME , Flores MS , Sepulveda - Saavedra J , Romero - Diaz VJ , Becerra - Verdin EM , Tamez - Rodriguez 15. Heath JW , Ueda S , Bornstein MB , Daves GD , Raine CS . VA , et al. An experimental model of peripheral neuro- Buckthorn neuropathy in vitro: evidence for a primary pathy induced in rats by Karwinskia humboldtiana neuronal effect. J Neuropathol Exp Neurol 1982 ; 41 : (buckthorn) fruit. J Peripher Nerv Syst 2006 ; 11 : 253 – 261 . 204 – 220 .

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