Exercise, Ethanol, and the Processes of Disease

or

If I bother staying active canI continue to drink?

by C. Murray Ardies, Ph.D.

Alcohol

Beverage alcohol is fecal matter. Alcohol is not made of grapes or grain or other attractive foods. It is these which are devoured by the ferment germ, and the germ then evacuates alcohol as its waste product. The thought of swallowing the excrement of a living organism is not an aesthetic idea but people will do such things

- Liquor, The Servant of Man Little Brown & Co. 1940

An alcoholic is someone who drinks too much, and you don’t like anyway.

- Anonymous

Alcoholic beverages have been known for many thousands of years with some evidence for both beer and berry wine being used over 6,000 years BC; some believe that mead was in use over 8,000 years BC.

Grape wine dates back to around 300 to 400 BC and consumption of beer is common throughout the entire world as observed by Columbus when he arrived on the shores of the Bahamas (and other of the “West Indies”).

Alcohol has not always been legal in the USA …

The formation of the American Temperance Society in 1827 provided a national forum for the many local temperance groups which flourished in the beginning of the 19th century.

The first prohibition-based law was passed in 1834 by congress; a law which prohibited the sale of liquor to Indians. In 1851 Maine passed a state-wide prohibition law and by 1855, 13 other states passed prohibition laws (only to be repealed by 9 of the states by 1868).

Over the next few decades many states passed prohibition laws and then repealed them but the political and religious views espoused by the National Prohibition Party (1869), the Christian Woman’s Temperance Union (1874) and the American Anti-Saloon League (1895) finally “took hold” and by 1907 the final movement toward all-out prohibition began…

It is difficult to believe, however, that this national movement was based on any real concern other than “the middle-class, rural, Protestant, evangelical concern that the good and true life was being undermined by ethnic groups with a different religion and a lower standard of living and morality” - Clark, N.H., The dry years: prohibition and social change in Washington. University of Washington Press, 1965)

Between 1907 and 1919 34 states passed prohibition laws … in 1917 the Senate (with Congress concurring soon after) submitted to the states the national prohibition amendment ... fully ratified by 1919 and enforced in 1920. Of course the effect of this movement was astounding:

From 1908 through 1917 over 104,000 licensed bars were closed while the per capita consumption of liquor increased by 16%. With the full impact of the prohibition amendment in 1920, consumption plummeted over 90% within the first year and then steadily rose through the ensuing decade. By 1933 the amendment was repealed and today the alcohol industry is a thriving 160+ billion dollar a year business.

Fermented beverages are made by mixing yeast with something that contains sugar and water. The yeast eats the sugar and evacuates alcohol; producing the alcoholic beverage. Concentration of alcohol in fermented beverages can range from 1%-3% to as high as 12%-14%. Higher concentrations of alcohol kills the yeast so you can’t get higher than that.

If the alcoholic beverage is then distilled (distillation was discovered in Arabia ca. 800 AD) to collect the alcohol it can be added back to the beverage (or other fluid of your choice) to get a higher concentration alcohol.

Alcohol is used by the majority of people in the USA.

From the National Household Survey of Drug Abuse, 2000 the following drinking frequency was observed:

Age Lifetime Past Year Past Month Past-Month/ Binge

12-17 41.7% 33.0 16.4 10.418-25 84.0 74.5 56.8 37.826-34 89.2 75.1 58.3 30.335+ 85.0 61.0 46.8 16.4

Of the approximately 180 million alcohol users in the USA, approximately 10% are heavy drinkers with about 2/3 of these being obsessive abusers (drinking alcoholics).

It doesn’t take much alcohol to make you impaired:

# of Drinks Body Weight (lbs)100 120 140 160 180 200 220

Blood Alcohol Level (mg%)1 .04 .03 .03 .02 .02 .02 .022 .08 .06 .05 .05 .04 .04 .033 .11 .09 .08 .07 .06 .06 .054 .15 .12 .11 .09 .08 .08 .075 .19 .16 .13 .12 .11 .09 .09

According to research on reaction time/movement time and driving skills, BAL’s as low as 0.02 significantly impair driving ability.

Ethanol produces inebriation by affecting both dopaminergic neurons and GABA (gamma-aminobuteric acid) receptors.

Ethanol activates the dopaminergic neurons of the ventral tegmental area which releases dopamine into the nucleus accumbens and most other components of the limbic system as well as to the frontal lobe. Enhanced dopamine levels in the limbic system are associated with a pleasurable feeling and this may account for some of the “good feelings” of mild intoxication.

VentralTegmental

Area

CaudateNucleus

Putamen

Globus Pallidus

Substantia Nigra

Piriform Cortex

NucleusAccumbens

Amygdala

Septum

Some FrontalCortex

Striatum

Ethanol also produces its effects by greatly enhancing the sensitivity of GABA (gamma-aminobuteric acid) receptors. GABA is the major inhibitory neurotransmitter in the brain and increased sensitivity of GABA receptors may account for the majority of the depressant effects of ethanol.

Both dopamine and GABA depress function of the basal ganglia which probably accounts for the impaired motor function while under the influence of ethanol. Impaired cognitive function may be due to both the inhibitory effects of dopamine release (from VTA activation) into frontal cortex and the general inhibitory effects of enhanced sensitivity to GABA.

The depressant effects of enhanced dopamine release and GABA sensitivity also are most likely responsible for the deadly effects of ethanol overdose. CNS function can be completely inhibited by the K+ release caused by dopamine (leading to neural hyperpolarization) and the Cl- uptake caused by GABA (also leading to hyperpolarization). Consumption of sufficient ethanol to produce a blood level of somewhere between 0.4 to 0.6 % (“chugging” around half-a-bottle or more – depending on body size) can lead to cessation of nerve function and death due to respiratory arrest.

With lower-dose consumption of ethanol on a regular basis, other much less noticeable but not much less deadly effects can occur.

Alcoholic Fatty Liveris the most common complication

of excess alcohol consumption

- Fatty liver is characterized by large fat deposits in the liver.

- Fatty liver is considered to be the first step in the development of Alcoholic Cirrhosis.

- Chronic Fatty Liver (reversible) progresses to Alcoholic Hepatitis (reversible) which, over a period of years, progresses to Alcoholic Cirrhosis (irreversible).

Normal Liver Fatty Liver

Alcoholic Fatty Liver to Alcoholic Cirrhosis -How Does it Work?

Two basic processes:

- Too much alcohol messes up function of liver cells by damaging proteins and decreasing synthesis of proteins; (especially noticeable in the mitochondria).

- Too much alcohol damages cell membranes leading to inflammation (as reviewed in the Introduction to Cells…

The big question is:How does alcohol cause the damage?

The currently accepted theory is that oxygen radicals are the main culprit.

The next questions are: Where do they come from? and, how do they cause damage?

Oxygen Radical Production by CYP

Hydroxyl radicals attack proteins and denature them, destroying their function.

Mitochondria produce much more oxygen radicalsthan normal when alcohol in present.

Oxygen radical damage to proteins in the mitochondria reduces metabolism of fatty acids and the presence of alcohol in the liver also reduces metabolism of fatty acids; leading to the accumulation of fat droplets in the cells.

Hydroxyl radicals attack the fatty acids on the membrane phospholipids causing leaky membranes.

An intact cell membrane acts as a barrier for (among other things) charged particles such as calcium.

A damaged cell membrane will allow (among other things) charged particles to enter the cell or organelle.

Regulation of Signal Transduction (S-T) Pathways

Activities of S-T pathways are regulated by a variety of growth factors, hormones, calcium, and ROS. Note that both Calcium and ROS affect enzymes that activate S-T pathways.

Thus control of Calcium and of ROS are very important for

controlling S-T.

If excessive S-T activity happens for an extended period of time (many hours to many days; or all the time…) then they will produce a variety of inflammatory signaling molecules that produces an inflammatory response…

Leading to even more disregulated S-T activity and more ROS…

©C. Murray Ardies, 2014

Oxygen radical damage to membranes leads to calcium entry into the cells which can trigger an inflammatory response while both the calcium and ROS stimulate the various S-T pathways… leading to hepatitis and if prolonged, cirrhosis.

So why is inflammation so bad when it is a process to defend against invading organisms and to initiate repair of damaged tissues?

- For the defense part, neutrophils kill organisms by generating lots of oxygen radicals and macrophages eat and digest organisms.

- For the repair part, cytokines stimulate the fibroblasts and epithelial cells to make scar tissue.

If these processes continue for many years lots of cells die and lots of scar tissue is formed. The end result is a very poorly functioning liver and a disease called alcoholic cirrhosis.

So, what can be done about the problem if you don’t want to quit consuming alcohol?

Two basic approaches should work:

A Increase the ability to repair damaged proteins.

B Decrease the amount of oxygen radicals.

A Cells have a set of proteins called heat-shock proteins which can renature oxygen radical damaged proteins. HSP70 is one of the major heat-shock proteins involved in this function. HSP73 is constitutive while HSP72 can be induced. Induction of HSP72 correlates with protection from radical-mediated changes in cell (protein) function.

Effect of Exercise and Ethanol onHSP70 Content of Liver Cells

Induction of HSP72 in the exercise + ethanol group should increase repair of proteins damaged by ROS

…Ardies ‘95

B Cells make antioxidant and redox-control enzymesto help get rid of the oxygen radicals and protect the cell.

SOD and CAT eliminate superoxide anions and peroxide to prevent (or greatly diminish) the production of the highly reactive hydroxyl radical.

Effect of Exercise and Ethanol onSOD and CAT Activity of Liver Cells

Maintenance of SOD activity and induction of CATactivity by exercise should reduce production of thehydroxyl radical and reduce oxidative damage.

… Ardies ‘97

With an increase in capacity to renature proteins damaged by ROS through induction of HSP72 and a reduction in oxidative damage due to an increase in SOD and CAT activity, mitochondrial function should be maintained and fatty liver prevented.

Effect of Exercise and Ethanol onMitochondrial Function of Liver Cells

… Ardies ‘87

One could even imagine that if ethanol clearance was faster, then less damage would occur because there would be less ethanol available over time to cause the damage.

… Ardies ‘1989

2.5(2.5, 3.5)

0(0)

0.5(0.5)

Fat content (median/mode) of liver from ethanol (A), control (B), and ethanol + exercise (C) treatments.

A B C

… Ardies ‘95

Thus, repeated exercise appears to prevent alcoholic fatty liver by enhancing antioxidant capacity, enhancing repair capacity, and maintaining mitochondrial function in liver.

So, if being fit, or actually, staying fit can help prevent alcoholic liver disease can it do anything else?

And, can alcohol consumption do something other than simply make us feel a little better (at times)?

Well … if one looks at the biological processes which lead to cancer, then one can see that a lot of the biological effects of exercise and some of those from ethanol consumption should greatly reduce risk for cancer as well.

So, what exactly is cancer?

- In essence, cancer is simply uncontrolled cell division.

- The terms neoplasm and tumor are often used to indicate a cancerous growth; ie: neoplasm ~ tumor ~ cancer.

- Cancer comes in two types: Benign and Malignant.

The process of developing cancer is generally called Carcinogenesis while the overall process is divided into three phases:

1. Initiation: Oxygen radicals or chemical radicals form adducts with DNA bases of Stem Cells. Unrepaired DNA damage leads to mutations in daughter cells following mitosis.

2. Promotion: Accelerated cell division leads to the accumulation of more mutations (less time to repair DNA) and clonal expansion of the mutated cells.

3. Progression: Accumulation of “appropriate” mutations leads to unrestrained cell division. Acquisition of additional “appropriate” mutations” leads to malignancy.

Obviously DNA damage is really important for causing mutations and cancer.

So, the big question is:

How is DNA damage caused? What does alcohol and exercise got to do with it anyway?

To answer the first question:

OXYGEN RADICALS CHEMICAL RADICALS (carcinogens)

REPAIR INFIDELITY

Maintaining DNA sequence is very important.

Oxygen radicals can lead to changes in DNA sequenceie. MUTATIONS.

Oxygen radical-caused mutations are very important in human cancer.

If one looks at LUNG CANCER, approximately 75% of all known mutations in the P53 gene are caused by oxygen-radical adducts while 43% are caused by bulky (chemical?) carcinogens (Harris, ’97). (Most cancers have both types of “mutations” so the percentage adds up to more than 100%).

So, what can exercise or ethanol do about this?

Effect of Exercise and Ethanol onSOD and CAT Activity of Lung Cells

…Ardies ‘97

Chemical radicals, aka carcinogens, also are important in causing DNA damage.

The majority of carcinogenic chemicals are not reactive in the form in which we are exposed to them.

They have to be metabolically activated to their carcinogenic form.

The enzymes which usually do this are our CYP enzymes.

So, if our CYP enzymes are making carcinogens out of the chemicals we ingest, is there a way to get rid of the active carcinogens once they are made?

And more importantly, can exercise or ethanol do anything about it?

One of the most active inactivation enzyme systems is the UDP-Glucuronosyl Transferases, especially for the tobacco-specific NNK carcinogens.

Effect of Exercise and Ethanol on

UDP-GT Activity of Lung Cells

…Ardies ‘97

So, when it comes to lung cancer issues, ethanol consumption seems to enhance antioxidant capacity of lung but not the elimination of active carcinogens.

Exercise, on the other hand, not only enhances antioxidant capacity of lung, but also increases the ability to inactivate active carcinogens…

an effect which appears to be even better with

drinking and exercise combined.

Some Summary Stuff

(Moderate) ethanol consumption is not known to be so good at reducing risk for cancers but is well-known for reducing risk for heart disease. This may be because heart disease is initiated predominantly by oxidative damage while cancer is initiated by both oxidative and chemical damage.

Exercise, on the other hand is known to reduce risk for both heart disease and cancer and may be due to the induction of both antioxidant enzymes and carcinogen-inactivation enzymes.

From these results it is clear that both exercise and (moderate) ethanol consumption should reduce risk for both diseases more than either one alone.

Of course, the exercise does seem to prevent alcoholic liver disease even in the face of large amounts of ethanol intake so maybe if you exercise enough, you don’t have to worry quite so much about the drinking???

So, how does it all work?

Appearance of the jun-fos heterodimer (AP-1) in the lung nuclei 4 hours after the start of 1-hour running exercise.

…Ardies ‘02

…Ardies ’02