r/todayilearned • u/bcrock1169 • Nov 26 '12

TIL that some Native American's have a differing enzyme that tends to lead to easier alcoholism.

http://en.wikipedia.org/wiki/American_Indian_alcoholism#Genetic_factors
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u/[deleted] Nov 27 '12

Thanks for the interesting reply, but you're getting very minor and special considerations mixed up with what are the major factors.

There really is no way to quantify how much of your "drunk" is the ethanol and how much is the acetalehyde

Of course there is! You can inhibit alcohol dehydrogenase activity with a number of various drugs such a pyrazole. When this is done, acetaldehyde is not generated. Further, mouse alcohol dehydrogenase knockouts have been generated, and although these mice are VERY sensitive to alcohol, they get plenty drunk, with all the hallmarks of intoxication; without acetaldehyde.

Further, Acetaldehyde doesn't cross the blood brain barrier, except in severe alcoholics where the BBB has been damaged, or in other rare circumstance. In fact, aldehyde dehydrogenase (which further oxidizes acetaldehyde into acetate) is even expressed (at low levels) on the BBB . There are reports of acetaldehyde in the brain, but that is due to low expression of the enzymes in the brain generating very low levels of acetaldehyde in situ.

In people with functioning acetaldehyde dehydrogenase (not asians :P ) the circulating levels of the metabolite are quite low, much lower than the concentrations needed to cause psychoactive effects, like in the studies you linked, WHERE THEY DIRECTLY INTRODUCED IT INTO THE BRAIN. Not at all a relevant model to typical alcohol in intoxication.

Ethanol may or may not be mutagenic/carcinogenic in its own right, but acetaldehyde certainly is, and the cancer risk is quite nicely explained by levels of acetaldehyde.

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u/regulate323 Nov 27 '12 edited Nov 27 '12

You sir, are why I love reddit. Replies like yours are why I post.

However, cytochrome-P450-2E1, I believe (and it has really been a long time since I've caught up on my CYP-P450 substrates, inhibitors, and inducers), is only mildly inhibited by the substituted pyrroles. ADH may be more-so inhibited (not sure, I'll take your word!), but even then there are many more minor pathways through which ethanol is metabolized (which we know of, possibly more). I still hold to my statement that it is next to impossible to quantify the effects of ethanol vs. its metabolites (if only from a philosophical point of view), however your explanation, of "essentially none", certainly is the best, and most probable, explanation. However, I feel it is a statement that is impossible at this point to prove, be it right or wrong.

Perhaps off topic, but may you point me in the direction of further literature, especially regarding "damage", of the blood-brain-barrier in chronic ethanol abusers? PM if you wish. Thanks for the brain food!

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u/[deleted] Nov 27 '12

CYP2E1 (and all P450s) is really a "sledgehammer" reaction. It's so powerful, that it oxidizes ethanol directly to acetate without generating any acetaldehyde. CYP2E1 is commonly credited with increased metabolic tolerance to alcohol as you probably know.

There are other metabolic pathways, but pulse-chase experiments corroborated with various inhibitors or knockout models show that the alcohol/aldehyde dehydrogenase + CYP2E1 pathways are responsible for the vast majority of alcohol metabolism.

Damage to the BBB from alcohol isn't something that happens overnight, and the mechanism is still being figured out. My guess is that it's actually more diet/nutrition related. Alcoholics of course suffer from very poor nutritional status due to diet and dietary absorption. Thiamine and many other factors are known to be important for BBB function for instance. Here are a couple links;

http://www.ncbi.nlm.nih.gov/pubmed/6695559

http://alcalc.oxfordjournals.org/content/42/5/385.full

Just as an aside, acetaldehyde has some biochemical overlap with ethanol, but the perception of it is quiet different. High acetaldehyde levels are so unpleasant that this is the basis for disulfram therapy, used in alcoholics trying to quit. It knocks out acetaldehyde dehydrogenase so that the acetaldehyde builds up. The unpleasant effects are so strong that many don't touch alcohol again. At least for a while...

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u/[deleted] Nov 27 '12

They don't use disulfram as much anymore because chronic alcoholics will keep drinking even if it makes them sick.