Molecule of the Day

Here’s a neat and weekend-appropriate one. I’ve alluded to the fact that your body processes small amounts of endogenous alcohol in the course of metabolism. As such, you have evolved some enzymes to process ethanol. The enzymes are meant for ethanol, since that’s what organisms saw for the most part in the course of evolution. As we’ve seen with drugs and poisons, though, other molecules can fit just fine into the active pocket of an enzyme and it can do its business on them, too. Sometimes this works in your favor, sometimes not. In the case of alcohol, it’s great. If you didn’t have a processing enzyme, it would be much more harmful than it is; it would have to wait around to pass through your urine (it could fit into a few other enzymes, but not very well; I believe this is the major alternative pathway).

What happens is your body takes alcohol and begins to oxidize it. Ethanol turns into acetaldehyde, which turns into acetic acid, which your body knows how to handle fine. The ethanol to acetaldehyde step is catalyzed by the enzyme alcohol dehydrogenase and requires one NAD+ (nicotinamide adenine dinucleotide, an endogenous oxidizing agent involved in glycolysis. The acetaldehyde to acetate step also requires NAD+ and is catalyzed by aldehyde dehydrogenase.
Relative to Anglos, many Asians have a paucity of aldehyde dehydrogenase, causing acetaldehyde to build up when ethanol is consumed. This causes the flushed face seen in many Asians after even moderate alcohol consumption. In all populations, NAD+ is limiting; your body simply does not have that much. It is regenerated, but slowly, so even after moderate alcohol consumption, NADH (the metabolite of NAD+) to NAD+ regeneration is the limiting step in the alcohol to acetate cycle. This is poorly understood — understandably. Not many research dollars get routed to hangover prevention, since it’s essentially a nuisance and considered a “disease of excess.”

Here are a few other alcohols; notice how they go through the same enzyme and conversion is analagous. Don’t hold me to the middle aldehyde steps in the conversion of ethylene and propylene glycol; there are surely half-oxidized intermediates. The ultimate metabolites are as shown, though:

As you can see, methanol is converted to formaldehyde, which is converted to formic acid. Both are profoundly toxic, and I am told the formic acid is what causes the blindness associated with MeOH ingestion. Ethylene glycol is found in many antifreezes. Aldehydes in general are quite reactive and can poison certain enzymes, but the real bugger here is oxalic acid. This forms insoluble complexes with calcium (for example) and is quite poisonous. I am told calcium oxalate can actually precipitate within your kidneys! Propylene glycol is often used for antifreeze now; as you see, it is converted to pyruvate, which is an intermediate in the Krebs/Citric Acid Cycle. As such, your body handles it quite nicely.

Previously, the treatment for ingestion of any foreign alcohol was ethanol intoxication! You would be given IV (or, rarely, oral) ethanol until the offending alcohol exited through the urine. This trick works because of the enzymes’ structures; they bind ethanol much more tightly than other alcohols, so the ethanol ties up the enzyme, keeping it from converting EtGly and MeOH (which aren’t that toxic in their own right; their metabolites are).

Like New Coke, Matt LeBlanc-starring role sitcoms, Mutual Assured Destruction, and countless other things that seemed like a good idea at the time, the days of free booze in the ER are coming to a close. Enter 4-methylpyrazole:

4-methylpyrazole binds to alcohol dehydrogenase even more tightly than ethanol, making it both a more effective and less toxic drug for non-ethyl alcohol poisoning. It is still not used universally though, so if you ever find yourself having drunk Sterno, you may be surprised by what the ER docs suggest doing. No entries until Monday - I’m switching to weekdays only.

Have a good Friday and weekend, and remember: If your alcohol is from the hardware store, it’s probably not for drinking.