Persin - Exploring the secret pharmacological life of the humble avocado

An important message for the under-the-table pet feeders of the world: If you feed your animal friend a bunch of avocado, it may get very sick [1]. This is thanks to a toxin called persin, which is found in both the fruit and leaves of the avocado tree (Persea americana). Persin is an polyketide that is made via the same biochemical pathways that the avocado plant uses to make its delicious, delicious fatty acids. In fact, it closely resembles linoleic acid, an essential omega-6 fatty acid.

For some reason, persin is usually harmless to humans (though it may be responsible for some avocado allergies) but can seriously mess with all sorts of other animals including birds, mammals (other than us), and fish. Lactating rodents and livestock that eat avocado leaves often develop udder-related problems such as inflammation and wonky milk secretion [2]. Avocado consumption has also been linked to heart damage (necrosis of myocardial fibres) in several mammals. This sort of selective toxicity is actually fairly common among drugs. For example, penicillin is pretty darn safe for humans (provided you aren't allergic), but it kills off guinea pigs like a gator in a...well, guinea pig factory. Keep this in mind the next time your little furry bundle of joy and frequent excretion gets an infection and requires black market antibiotics.

Persin is also capable of harming fungi and insects, particularly those species that infect/eat the avocado plant (e.g. Colletotrichum gloeosporioides, which also attacks citrus fruits and papayas). This may explain why the compound exists in the first place!

In keeping with its toxic nature, persin is capable of killing breast cancer cells (hooray!). Not only that, it can boost the effects of tamoxifen, a popular breast cancer drug [3]. This synergistic effect is thought to be in part due to persin messing with steroid hormone receptor signaling so as to make breast cancer cells more susceptible to the estrogen receptor modulatory effects of tamoxifen.

[1] Buoro IB, Nyamwange SB, Chai D, Munyua SM. (1994). Putative avocado toxicity in two dogs. Onderstepoort J Vet Res. 61(1):107-109.
[2] Oelrichs PB, Ng JC, Seawright AA, Ward A, Schäffeler L, MacLeod JK. (1995). Isolation and identification of a compound from avocado (Persea americana) leaves which causes necrosis of the acinar epithelium of the lactating mammary gland and the myocardium. Nat Toxins. 3(5):344-349.
[3] Roberts CG, Gurisik E, Biden TJ, Sutherland RL, Butt AJ. (2007). Synergistic cytotoxicity between tamoxifen and the plant toxin persin in human breast cancer cells is dependent on Bim expression and mediated by modulation of ceramide metabolism. Mol Cancer Ther. 6(10):2777-2785.

Je suis le lazy, so here are some free toxin review articles to read

I'm so not feeling the whole let's read a couple of papers and write a sweet-ass blog post vibe this evening, so instead I've decided to compile a list of comprehensive, well written, and most importantly, free review articles covering various types of toxins (poisons produced by living things). Think of it as if I've expertly written an entire series of concise posts, while avoiding any attempts at wit or humorous digression, and then lumped them together according to type into nice looking articles that I've linked below.

Bennett JW, Klich M. Mycotoxins. Clin Microbiol Rev. 2003 Jul;16(3):497-516. Review.

Van Dolah FM. Marine algal toxins: origins, health effects, and their increased occurrence. Environ Health Perspect. 2000 Mar;108 Suppl 1:133-41. Review.

Terlau H, Olivera BM. Conus venoms: a rich source of novel ion channel-targeted peptides. Physiol Rev. 2004 Jan;84(1):41-68. Review.

Kini RM. Anticoagulant proteins from snake venoms: structure, function and mechanism. Biochem J. 2006 Aug 1;397(3):377-87. Review.

Daly JW. The chemistry of poisons in amphibian skin. Proc Natl Acad Sci U S A. 1995 Jan 3;92(1):9-13. Review.

Middlebrook JL, Dorland RB. Bacterial toxins: cellular mechanisms of action. Microbiol Rev. 1984 Sep;48(3):199-221. Review.

Can watermelon help keep your cucumber crisp?

Word is on the street that watermelon (Citrullus lanatus), God's gift to summertime family reunions, may produce a Viagra-like effect. As a commenter on reddit put it: "They cool you above and fire you up down below."

This effect is apparently made possible by an amino acid called citrulline, which is found in both the rind and flesh of the watermelon. It's also found in mammals, where it is present as a free molecule in the liver as an intermediate in the urea cycle (toxic ammonia in blood -> urea in kidney -> you pee it out) and occasionally found incorporated into proteins. As it is not coded by DNA, it must be produced via the post-translational (occurring after a protein is synthesized from amino acids) modification of arginine, a structurally related amino acid. This process is called citrullination, and it occurs primarily in proteins found in myelin or involved in keratinization (deposition of keratin in skin, hair, and nails). Insufficient citrullination of these proteins has been implicated in some autoimmune diseases including rheumatoid arthritis, psoriasis, and multiple sclerosis.

Anyway, back to this watermelon = possible stiffy business. Following the consumption of watermelon, the citrulline it contains is enzymatically converted into arginine, which in turn is broken down to release a gas called nitric oxide (NO). NO causes the smooth muscle within the walls of blood vessels to relax, leading to dilation of affected vessels and increased blood flow through them. Increased blood flow to the penis leads to an erection. Sounds good, right?

Now here's the thing. Lots of substances can dilate blood vessels, including alcohol and chocolate. We synthesize citrulline in our guts from glutamine, a much more common amino acid. Dairy products, meat, seafood, bread, oatmeal, nuts, seeds, and lentils all contain decent amounts of arginine, which is what citrulline is converted to before it becomes NO. Viagra is so good at doing what it does because it acts on a particular enzyme that opposes the action of NO and is found almost exclusively in the penis. Just because something dilates blood vessels and increases blood flow doesn't mean its going to produce a woody.

The way I figure it, either the researchers at Texas A&M wanted some publicity and so went out of their way to mention that watermelon could potentially be used to treat erectile dysfunction, or the media decided to concentrate on the sex and ignore the science. Possibly both.

It should be mentioned that even if this whole watermelon boner thing is bogus, drugs that relax blood vessels are important for the treatment of many cardiovascular issues such as angina and hypertension. Citrulline is currently used to treat inherited urea cycle disorders and may eventually find use as a means of boosting the citrullination of proteins implicated in autoimmune diseases.

- Curis E, Nicolis I, Moinard C, Osowska S, Zerrouk N, Bénazeth S, Cynober L. Almost all about citrulline in mammals. Amino Acids. 2005 Nov;29(3):177-205. Review.