Toxalbumins - Peas and beans gone bad

Toxalbumins are protein phytotoxins (toxins produced by plants) capable of inhibiting protein synthesis, which is kind of a really bad thing to have happen to you. They are technically a type of ribosome-inactivating protein (RIP, a most suitable acronym), but more on that later.

Rosary PeaAbrin is a toxalbumin made by Abrus precatorius (Rosary Pea, Crab's Eyes, Jequirity), a vine that produces pea-sized bright red with a black splotch seeds that are used as beads and to make rattles. These seeds, although chock full of abrin, have a hard water-resistant coat, meaning that if you ingest them they are only toxic if they are chewed or broken.

Castor BeanRicin is a toxalbumin present in the seeds (beans, although not true beans) and other parts of Ricinus communis (Castor Bean). It is by far one of the easiest chemical warfare agents to obtain, since the plant grows all over the place (it's a common weed in North America) and the extraction of the toxin is relatively simple.

MistletoeViscumin and phoratoxin are toxalbumins produced by species belonging to the genera Viscum and Phoradendron, respectively. Both are mistletoes, those wonderful Christmas plants that enable public displays of affection and parasitize trees. Apparently mistletoe evolved independently five times, meaning that there are five different families of it. Viscum album (European mistletoe) is featured in Greek and Celtic mythologies and was the original Christmastime decoration, while Phoradendron serotinum (Eastern Mistletoe) is the main species grown and used by those in North America during the season of giving.

Other toxalbumins include: crepitin (aka hurin), found in the seeds of Hura crepitans (Sandbox tree), a tropical evergreen tree that produces numerous pointed spines on its trunk and pumpkin-like fruits that explode with considerable kaboom on drying; curcin (aka jatrophin), found in the seeds of species of the genus Jatropha, a New World shrub; momordin, found in the seeds and outer rind of the fruit produced by species of the genus Momordica; and robin and phasin, present in the bark, leaves, and seeds of Robinia pseudoacacia (Black Locust), a tree native to the United States with pretty little white flowers.

As I mentioned previously, toxalbumins are toxic because they inhibit protein synthesis. They accomplish this in a neat way. Each one is a dimer made up of two subunits, simply designated A and B. To spice things up, I will refer to them Albert and Betty. Albert is the actual toxin, while Betty is a lectin (carbohydrate-binding protein) that helps get him inside cells by binding to the cell membrane. Many plants produce Albert, but without Betty, he's just a harmless old fart. Once inside a cell, Albert is able to selectively catalyze the cleavage of an N-glycosidic bond in the 28S ribosomal RNA that is a crucial part of eukaryotic ribosomes, the things inside cells that make proteins, thus inhibiting their formation and essentially shutting down the cell. A single molecule of one of these toxalbumins is capable of inactivating thousands of ribosomes. Ribo oh no! Since people are generally exposed to these things via ingestion, their first site of action tends to be the rapidly proliferating cells of the intestinal wall.

Poisoning proceeds as follows. First there is a latent period, in which nothing appears to be happening. In actuality, the toxin is hard at work, shutting down ribosomes. Then things start to happen. Time to get out your catastrophic health insurance card and head to the hospital. A little nausea, some vomiting and diarrhea. Some victims develop ulcerative lesions throughout their GI tract. The gastric mucosa starts to hemorrhage. Total disruption of intestinal function leads to massive fluid and electrolyte loss, and death soon follows.

- Lampe KF and McCann MA. AMA Handbook of Poisonous and Injurious Plants. American Medical Association, Chicago, 1985.
- Hui A, Marraffa JM, Stork CM. A rare ingestion of the Black Locust tree. J Toxicol Clin Toxicol. 2004;42(1):93-5.

- The pretty pictures were taken by deadmike, M Kuhn, and Randy Read.


Cerberin - To hell and back again

Deep in the coastal salt swamps of south India, there grows a species of tree. This tree, though taxonomically classified in Latin as Cerbera odollam, is known by most as the Suicide tree [1].

Plants belonging to the genus Cerbera are wonderfully toxic. They get their name from Cerberus, the hellhound of Hades in Greek mythology. The primary toxin responsible for the toxicity of Cerbera species is cerberin, a digoxin-like cardiac glycoside that is capable of royally messing up your heart [1]. Now, digoxin is a useful drug. It can be used to treat a whole lot of heart problems, including atrial fibrillation/flutter. Problem is, you give too much of it, and suddenly it starts causing things like ventricular fibrillation and heart block. Things that are fatal.

Cerberin has a couple of properties that make it an attractive poison. It is difficult to detect the toxin in dead people without real fancy (and expensive) chromatography and spectrometry, and the taste of the plant can be hidden with the use of potent spices [1].

[1] Gaillard Y, Krishnamoorthy A, Bevalot F. (2004). Cerbera odollam: a 'suicide tree' and cause of death in the state of Kerala, India. J Ethnopharmacol. 95(2-3):123-126.


Penicillamine (Cuprimine, Depen) - For when the copper is gettin' you down

  • metabolite of penicillin, but is not an antibiotic since it lacks a beta-lactam ring
  • discovered in 1953 in the urine of people with liver disease who were being given penicillin
  • a fellow named John Walshe did some nifty experiments and figured out that it facilitated the excretion of copper via the urine, making it a useful agent for the treatment of Wilson's disease
    • Wilson's disease is this genetic thing where people can't effectively rid themselves of copper, causing the metal to accumulate in the organs (e.g. brain and liver) and cause damage (e.g. dementia, mood disorders, Parkinson's-like symptoms, and hepatitis with cirrhosis developing over time)
  • penicillamine functions as a chelating agent, meaning that it forms complexes with certain metal ions and promotes their elimination from the body via the urine
  • used to treat the following:
    • rheumatoid arthritis, scleroderma, and primary biliary cirrhosis (opens up a can of selective whoop-ass on your immune system)
    • cystinuria (facilitates the elimination of cystine)
    • mercury and lead poisoning (same valences as copper, yo)
    • the aforementioned Wilson's disease (i.e. copper poisoning)
  • only the D-isomer (get the lowdown on chirality) is used as a drug since the L-isomer can poison you by inhibiting the good stuff that vitamin B6 (pyridoxine) does
Goodman & Gilman's The Pharmacological Basis of Therapeutics - 11th Ed. (2006)


Book Review: Goodman and Gillman's The Pharmacological Basis of Therapeutics (1st ed, 1941)

I purchased this book online from a used book seller earlier this month, and it arrived at the local post office a couple of days ago. After braving a cold walk to and from the drug store (Shoppers Drug Mart and Canada Post got some sort of shifty agreement going), I tore open the parcel with nothing more than my bare hands and dumped into my lap the first edition of what is known to many as the bible of pharmacology. Thus, I fulfilled a life-long dream, and my existence was rendered somewhat more complete. After a quick inspection and subsequent sigh of relief (the name of some doctor in the front, but no annoying underlining or notes, and the binding is solid), I delved in. Well, actually, I made dinner and watched a bit of television first. I know my priorities.

This tome, among other things, serves as a fantastic time capsule for the state of pharmacology (and toxicology) in the late 1930s (it was published in 1941). There are three chapters on drugs used to kill syphilis, but no mention of penicillin. No discussion of statins or oral hypoglycemics, and no chapters on antidepressants, antivirals, immunomodulators, or cancer chemotherapy!

We've come a long way.

Goodman and Gillman actually took the time to write up a brief history for each the classes of drugs they describe in their book. I think it's my favourite part. Subsequent editions have have updated the history bits, but I like reading about what had transpired up until 1941. Incidentally, if any of you know of any good old pharmacology or toxicology history books, I'd love to hear from you.

All in all, completely out of date, but if you want a cool and relatively cheap old science book to help fill up your shelves and make you look interesting and sophisticated (read: both a science and old book nerd), search out this book.

Drug screening can refer to the drug tests that employers and hospitals perform on people, as well as to finding out information on drugs, such as their potential to be metabolized by the liver into toxic derivatives. Tests are usually a urine or hair drug test, which are established methods. A number of resources on hair drug testing are available. Should you be addicted to drugs, treatment options are available.


Montelukast (Singulair) - Alleviating allergies and asthma

  • leukotriene receptor antagonist (LTRA) used to treat persistent asthma (the best kind!), allergic rhinitis (hay fever), and exercise-induced bronchoconstriction (i.e. your throat closing up after a nice jog around the neighbourhood)
  • causes bronchodilation (throat opening up) and prevents inflammation by blocking the nasty bronchoconstricting and proinflammatory effects of leukotrienes
  • at the molecular level, prevents cysteinyl leukotrienes (C4, D4, and E4) from binding to type 1 cysteinyl leukotriene receptors
  • can be taken orally (as a pill) only once or twice per day, which makes it an attractive alternative to puffers (inhaled corticosteroids)
    • puffers are way cooler though
  • use of montelukast has been associated with the development of Churg-Strauss syndrome
  • similar drugs include zafirlukast (Accolate) and pranlukast (in Japan only)
  • there are many people who suffer from alcohol and substance abuse that go without dual diagnosis rehab, and there are many rehab facilities like California drug detox centers that have helped many people with drug treatment programs
- Keogh KA, Specks U. Churg-Strauss syndrome: clinical presentation, antineutrophil cytoplasmic antibodies, and leukotriene receptor antagonists. Am J Med. 2003 Sep;115(4):284-90.
- Lipworth BJ. Leukotriene-receptor antagonists. Lancet. 1999 Jan 2;353(9146):57-62. Review.
- Storms W. Update on montelukast and its role in the treatment of asthma, allergic rhinitis and exercise-induced bronchoconstriction. Expert Opin Pharmacother. 2007 Sep;8(13):2173-87. Review.
- http://en.wikipedia.org/wiki/Montelukast


Mesna (Mesnex, Uromitexan) - Terminator of thiols

  • also called sodium 2-mercaptoethanesulfonate, but mesna sounds way cooler
  • given during cancer chemotherapy involving oxazaphosphorine drugs like ifosfamide and cyclophosphamide to prevent damage to the bladder and kidneys, which can result in hemorrhagic cystitis
    • it is thought that mesna is able to bind up toxic metabolites of the cancer drugs that have been filtered out by the kidneys
    • hemorrhagic cystitis is inflammation of the linings of the bladder and kidneys resulting in bleeding, which can present as blood in the urine (haematuria)
  • contains a thiol (sulfhydryl) group, which enables it to release thiol-containing compounds that have become bound to proteins via disulfide bonds by exchanging itself with the compound
    • increased release of these thiol-containing compounds from proteins leads to their increased excretion and lowered blood levels
      • homocysteine is produced by the breakdown of methionine, another amino acid
      • an elevated level of homocysteine in the blood has been positively associated with atherosclerosis
  • also reduces oxidative damage induced by reperfusion following ischemia in the kidneys and intestine
  • if you are starting a new job, drug testing can be a source of major anxiety
- Urquhart BL, Freeman DJ, Spence JD, House AA. Mesna as a nonvitamin intervention to lower plasma total homocysteine concentration: implications for assessment of the homocysteine theory of atherosclerosis. J Clin Pharmacol. 2007 Aug;47(8):991-7. Epub 2007 Jul 5.
- Ypsilantis P, Lambropoulou M, Tentes I, Kortsaris A, Papadopoulos N, Simopoulos C. Mesna protects intestinal mucosa from ischemia/reperfusion injury. J Surg Res. 2006 Aug;134(2):278-84. Epub 2006 Feb 28.
- http://en.wikipedia.org/wiki/Mesna