LONG - New Scientist article on acetaldehyde

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It's hard to look fetching with a hangover. Curtains closed, you lie

in bed with a parched mouth, pounding head and queasy stomach. On

your way to the kitchen for a glass of water you catch sight of

yourself in a mirror. Not a pretty sight. And if you could witness

the state of your insides you'd be even more horrified.

You are probably blaming your haggard state on dehydration, or

impurities in whatever it was you drank last night, but you're only

partly right. Another big reason for your hangover is a simple

molecule called acetaldehyde, produced by your liver as it breaks

down ethanol. You can take comfort from the fact that once the

acetaldehyde has cleared from your system you will feel a lot better,

but your internal organs aren't so lucky. They will be feeling the

effects of acetaldehyde for much longer.

For a long time, acetaldehyde was thought to be a harmless

intermediate in the breakdown of ethanol and was pretty much ignored.

Then its sinister edge began to emerge. It started in the 1980s when

alcohol researcher Victor Preedy of King's College London found that

acetaldehyde is a powerful muscle poison, roughly 30 times more toxic

than ethanol itself.

It has since become clear that acetaldehyde is the real demon in the

demon drink. For 30 years researchers have known that excessive

alcohol intake causes serious long-term damage to virtually every

internal organ: brain, kidneys, gonads, skeletal muscle, liver,

heart, uterus and digestive system. The assumption was that ethanol

itself was to blame, but the mechanism was unclear. Now, as we find

out more about how drink wreaks long-term havoc, the spotlight is

increasingly moving away from ethanol and towards acetaldehyde.

It's not just our boozing habits that are to blame. Tobacco smoke,

exhaust fumes and foods all contribute to your acetaldehyde load. The

bacteria living in your mouth and guts churn it out in bucket loads.

The onslaught on your body comes from within and without.

Measuring overall acetaldehyde exposure is tricky as the molecule is

quickly broken down in the body, but researchers now believe that

acetaldehyde is at least partly responsible for the rising incidence

of cancer and liver disease as well as, possibly, Alzheimer's.

For such an innocuous-looking molecule, acetaldehyde is surprisingly

toxic. " With the kind of levels we take in, most of us should be

dead, " says Deitrich, a pioneer in acetaldehyde research at

the University of Colorado Alcohol Research Center in Aurora.

Fortunately, the body has a battery of detoxifying enzymes that

specialise in breaking the stuff down.

Almost every tissue in the body is equipped with the enzymes known as

aldehyde dehydrogenases (ALDHs), which convert acetaldehyde to

harmless acetic acid. There are 19 different ALDHs in humans but one

in particular, ALDH2, does most of the work - especially in the liver.

As soon as you start drinking alcohol, your liver revs into action.

First, it converts the ethanol into acetaldehyde using another

enzyme, alcohol dehydrogenase. Acetaldehyde is then broken down by

ALDH2 and the resulting acetic acid is burned as fuel in the muscles.

The liver does a fantastic job: normally it eliminates over 99 per

cent of the acetaldehyde. Only minute amounts escape into the

bloodstream. But that's where the problems start.

The average liver can process about 7 grams of ethanol an hour -

though in heavy drinkers that figure can rise to 10 grams - meaning

that it takes about 12 hours to eliminate all the ethanol in a bottle

of wine. That's 12 hours of continuous exposure to acetaldehyde,

possibly longer. " It remains to be solved how fast acetaldehyde

disappears, " says alcohol researcher sson from Finland's

National Public Health Institute in Helsinki.

Irreversible damage

What is becoming increasingly clear is that almost any exposure to

acetaldehyde can do serious damage. Acetaldehyde attaches itself to

amino groups in proteins to form stable compounds called adducts.

According to Onni Niemelä of the University of Tampere in Finland,

these cause irreversible damage by messing up protein structure and

function. In the wake of a drinking bout, a whole range of adducts

are formed in the liver, muscles, heart, brain and gastrointestinal

tract.

Skeletal muscle is particularly badly affected. Preedy has found that

rats given a single dose of ethanol end up with significant muscle

damage as a result of acetaldehyde attacking proteins. The changes

persist for more than 24 hours, long after the chemical itself has

disappeared from the system (Alcohol and Alcoholism, vol 40, p

485). " It's a common misconception that the brain and the liver are

the two organs most affected by alcohol abuse, " says Preedy. " Muscle

damage is the most common. " Among alcoholics, he says, muscle damage

is five times more common than cirrhosis of the liver.

To make matters worse, the immune system sees these adducts as

foreign and fires off an inflammatory response. Around 70 per cent of

patients with alcoholic liver disease have anti-acetaldehyde

antibodies in their bloodstream. Drumming up an inflammatory response

is usually considered a bad omen as it can result in cell injury and

persistent inflammation. It has been linked with a host of diseases,

including rheumatoid arthritis, heart attacks, Alzheimer's disease

and cancer (New Scientist, 22 May 2004, p 40).

Acetaldehyde also attacks DNA. In 2005, researchers at the US

National Institute on Alcohol Abuse and Alcoholism in Bethesda,

land, reported that acetaldehyde can attack DNA in much the same

way it does proteins. The resulting adducts disrupt DNA's structure

and function, and can trigger mutations and chromosomal problems

(Nucleic Acids Research, vol 33 p 3513). These adducts have shown up

in the organs of rodents fed alcohol and also in the white blood

cells of alcoholics. Little wonder, then, that although ethanol

itself is not considered a carcinogen, acetaldehyde is - at least in

animals.

There is growing evidence that acetaldehyde is a human carcinogen

too. Some of the best evidence comes from studying people who cannot

process the compound normally. Roughly 50 per cent of people of

Japanese, Chinese, Korean or Taiwanese origin carry at least one

faulty copy of the ALDH2 gene and can scarcely break down

acetaldehyde at all. The mutation is dominant so even having one copy

causes problems.

Flushed faces

The immediate consequences of having the faulty version of the ALDH2

gene are highly visible. " You can see it in any restaurant in Japan

or China, " sson says. Almost as soon these people have an

alcoholic drink, their acetaldehyde levels shoot up to between 6 and

20 times that found in people with normal ALDH2. This

acetaldehyde " rush " triggers facial flushing, elevated heart rate and

dilated blood vessels. Dizziness, headache, nausea and vomiting soon

follow.

Not surprisingly, most flushers tend to avoid alcohol, which is just

as well since the long-term health consequences are turning out to be

serious. Among the minority of flushers who are also heavy drinkers,

the incidence of upper gastrointestinal tract cancer is about 50

times the normal rate. Gene-deficient people also have high rates of

head and neck cancer.

There's more. A recent study of 818 heavy drinkers in Germany found

that those individuals who are exposed to more acetaldehyde as a

result of a genetic defect - in this case, in the gene for alcohol

dehydrogenase - are at greater risk of developing cancers of the

upper gastrointestinal tract and liver (International Journal of

Cancer, vol 118, p 1998). These and a host of other results all add

to the growing suspicion that acetaldehyde is a human carcinogen,

says Helmut Seitz, professor of alcohol research at the University of

Heidelberg in Germany. Mikko Salaspuro, a gastroenterologist at the

University Central Hospital of Helsinki, agrees. " It is likely that

acetaldehyde will soon be considered to be carcinogenic in humans, "

he says.

Acetaldehyde also seems to play a role in breast cancer, with up to 5

per cent of all breast cancers attributable to alcohol

consumption. " The cells don't forget. This will initiate tumours 20

to 25 years later, " says Seitz, who is convinced that escalating

alcohol intake in the west is linked to rising rates of liver, colon

and rectal cancer.

There are even suggestions of a link between acetaldehyde and

Alzheimer's disease. In 2004, researchers at Nippon Medical School in

Kawasaki, Japan, reported that among a group of people with

Alzheimer's, the faulty version of ALDH2 was significantly more

common than among a randomly chosen group of healthy people of the

same age (ls of the New York Academy of Sciences, vol 1011, p 36).

So who is at risk? As a general rule, most of the excess acetaldehyde

you encounter comes from alcohol, and the more alcohol you drink the

more acetaldehyde you are exposed to. There is no absolutely safe

level of consumption. " It is not necessary to drink huge amounts of

alcohol - even low amounts of ethanol taken regularly in a sensitive

person increases their risk, " Seitz points out.

It's also worth bearing in mind that many alcoholic drinks contain

acetaldehyde from the word go. Sherry producers, for instance,

encourage acetaldehyde production for its fruity aroma. Calvados is

particularly rich in acetaldehyde, and regular calvados drinkers have

twice the incidence of oesophageal and oral cancer compared with wine

drinkers who consume the same amount of alcohol.

It gets worse. If you smoke, or are exposed to other people's smoke,

your acetaldehyde load rises further. Burning tobacco creates

acetaldehyde that dissolves in saliva, and acetaldehyde in saliva is

a big problem. Unlike the liver with its detoxifying enzymes, the

mouth's mucous membranes are pretty poor at breaking down

acetaldehyde. As a result, the toxic effects persist for longer.

Among smokers, the risk of oral cancer is 7 to 10 times higher than

for people who have never smoked. There are, of course, dozens of

carcinogens in tobacco smoke, so acetaldehyde may well not be the

only culprit. Nevertheless, an individual smoker's cancer risk is

strongly associated with acetaldehyde levels in their saliva and some

researchers now believe that acetaldehyde may be one of the principal

carcinogens in cigarette smoke.

Combine tobacco and alcohol and the danger multiplies. The effect is

synergistic, according to Salaspuro. This could explain the 150-fold

rise in oral cancers seen in people who are both alcoholics and

smokers, compared with those who abstain from both. " I don't know of

any other cancers in which the associations are so strong, " Salaspuro

says.

Diet dilemma

Acetaldehyde in saliva also comes from the bugs that colonise the

mouth and digestive tract. Many of these churn out acetaldehyde as

part of their normal biochemistry. Others absorb ethanol from

alcoholic drinks and turn it into acetaldehyde. Some people harbour

organisms that are particularly good at producing acetaldehyde. " It

depends on the kinds of flora you have. There may be huge variations

between individuals, " says Salaspuro. One mouth-dwelling bug,

Streptococcus salivarius, is particularly good at tossing out

acetaldehyde. Another, Neisseria, produces 100 times more

acetaldehyde when exposed to ethanol compared with other

microorganisms isolated from the mouth.

Microbial acetaldehyde production could also explain why people with

poor dental hygiene have an increased risk of mouth cancer. The

Finnish researchers collected saliva samples from 132 volunteers who

differed not only in their drinking and smoking habits but also in

the standard of their dental hygiene. The results show that poor

dental hygiene comes with a twofold increase in acetaldehyde levels

(Oral Oncology, vol 37 p 153).

Then there is acetaldehyde in the diet. For centuries, peoples have

used bacterial fermentation to produce food - everything from pickles

and yogurts to bread and cheese. Where there is fermentation there is

acetaldehyde. Acetaldehyde also occurs naturally in ripe fruit and

coffee.

" Companies making dairy products sometimes try to increase the

acetaldehyde level to give it a special aromatic taste, " says

Salaspuro. " Some yoghurt producers are searching for new bacteria

that are even better acetaldehyde producers. " And if you live in a

city, there's more. Acetaldehyde is spewed out by vehicle engines.

Air pollution adds to the toxic load, though nobody is quite sure how

much this affects our health.

With acetaldehyde - and evidence of its toxicity - coming at us from

all sides, it's not surprising that scientists are busy developing

ways to neutralise the threat. Salaspuro and colleagues at the

University of Helsinki, for example, are developing a chewing gum

that mops up acetaldehyde. The gum contains a harmless amino acid, L-

cysteine, which reacts with acetaldehyde and removes it from saliva.

Last year the team released a study showing that a piece of gum

containing just 5 milligrams of l-cysteine could totally eliminate

acetaldehyde from saliva if chewed while smoking (Cancer

Epidemiology, Biomarkers & Prevention, vol 15, p 146). Salaspuro

hopes the gum could help prevent digestive tract cancers in those who

are most at risk. The gum is being commercialised by a Finnish

company called Biohit.

Germ-busting mouthwash could also help. Mouthwash containing the

antiseptic chlorhexidine has been shown to slash the numbers of

acetaldehyde-producing microorganisms in the mouth, and in a study

with 10 volunteers, the Finnish researchers found that treatment with

chlorhexidine for three days cut acetaldehyde levels in drinkers'

saliva by 40 per cent.

Another solution proposed by the Finnish team is to tinker with the

bugs living in your intestines using prebiotics or probiotics.

Lactulose - a harmless, indigestible sugar - is one candidate for the

job, says Salaspuro. In experiments with rats, lactulose appears to

inhibit acetaldehyde production by making the colon more acidic.

Alternatively, ingesting a dose of living microorganisms that don't

produce acetaldehyde, such as some Lactobacillus and Bifidobacterium

species, could also help, say Seitz and Salaspuro.

None of these interventions has been shown to prevent cancer, so

cannot as yet be recommended as a substitute for a healthy lifestyle.

There is still only one sure route to an acetaldehyde-free life: keep

it clean. Scrub your teeth, avoid smoke, and next time you're

recovering from a hangover, remember to promise your internal organs

that this time really will be the last.

From issue 2590 of New Scientist magazine, 12 February 2007, page 30-

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