Alcohol Metabolism Break Down and Removal Mohamad Nusier MD. PhD.

In the United States, approximately deaths are attributed to alcohol abuse each year. In 2009, the World Health Organization listed alcohol use as one of the leading causes of the global burden of disease and injury. Alcoholic liver disease, a direct result of chronic alcohol abuse, insidiously destroys the normal functions of the liver. The end result of the disease, cirrhosis, ends in a dysfunctional and diffusely scarred liver. Introduction

Alcohol Metabolism and the Liver The liver is the principal organ for alcohol metabolism. The body naturally recognizes ethanol alcohol as a foreign, toxic agent that can disrupt normal homeostasis. When ethanol is consumed, it is rapidly absorbed by the upper gastrointestinal tract. Ethanol is diffused throughout the body, but exposure is greatest to the liver, via the main portal vein. Ethanol is metabolized by the body in the gastric mucosa and the liver. These organs manage an enzyme referred to as alcohol dehydrogenase, which is used by the body to oxidize ethanol and convert it into acetaldehyde and other metabolites. Acetaldehyde ultimately is converted by the body into acetic acid, and then acetate. Acetaldehyde affects protein synthesis.

The enzyme alcohol dehydrogenase plays a central role in the most ancient form of biotechnology: alcoholic fermentation. Yeast and many bacteria produce alcohol dehydrogenases. These microbial enzymes catalyze the last step in the conversion of food into metabolic energy, creating ethanol. Sugars are broken down and used for energy, forming ethanol as the waste product, which is excreted into the liquid surrounding the cell. Humans harnessed this process to produce alcoholic beverages: yeast is allowed to ferment grain sugars to form beer, and yeast is allowed to ferment grape juice to form wine. Alcohol

Microbial ADH Tetramer 4 x 352 amino acid residues 4 zinc ions (Zn ++ ) 4 NAD cofactors

Human ADH Homodimer (two molecules) 2 x 373 amino acid residues 6 zinc ions (Zn ++ ) 2 NAD cofactors

Human ADH Microbial

Small Amounts Unmetabolized (10%) Excreted with l Sweat l Urine l Breath

1st Pass Metabolism l Occurs in the Stomach l Gender Differences Exist: Men have a higher level of ADH than women l Early metabolism translates to lower Blood Alcohol (BAC) levels

2nd Pass Metabolism l Occurs in the Liver l 1st liver enzyme--Alcohol Dehydrogenase (ADH)-----> Acetaldehyde l 2nd liver enzyme--Acetaldehyde Dehydrogenase----> Acetic Acid l Acetic Acid oxidized by body organs----> CO 2 + H 2 O

Blood Alcohol Concentration l The Ratio of Alcohol in the blood to the total volume of blood expressed as % l The presumptive level of intoxication = 0.10% l FOR A 75 Kgs. Individual each drink =.02% l *One drink is 14 gm pure alcohol

PROBLEM l If an individual weighing 75 Kgs. consumes 2 drinks per hour, what will his/her BAC level be at the end of that time?

SOLUTION Hour 1: = =.02% Hour 2: = =.04% Hour 3: = =.06% Hour 4: = =.08% Hour 5: = =.10% DUI

ALCOHOL’S EFFECT ON THE BODY l DIGESTIVE SYSTEM: IRRITANT INCREASING AMOUNTS DISTRUPT OR STOP DIGESTION PYLORIC VALVE MAY BE EFFECTED “STUCK”

ALCOHOL’S EFFECT ON THE BODY l CIRCULATORY SYSTEM MINOR EFFECTS Heartbeat & blood pressure little effect, unless…. Vasodilator of surface vessels Body heat loss (HYPOTHERMIA)

ALCOHOL’S EFFECT ON THE BODY l KIDNEYS Increased urine output CONSUMING LARGE QUANTITIES OF LIQUID REDUCES THE PITUITARY HORMONE ADH (ANTIDIRURETIC HORMONE)

ALCOHOL’S EFFECT ON THE BODY l LIVER Eliminates liver production of glucose creating HYPOGLYCEMIA Brain deprived of proper NOURISHMENT Weakness, Nervousness, Sweaty, Headache, Tremors FATTY LIVER

ALCOHOL’S EFFECT ON THE BODY l WHITE BLOOD CELLS ACUTE ALCOHOL CONSUMPTION SUCH AS BINGE DRINKING HAS A DIRECT EFFECT ON: WBC RESERVES CHEMOTAXIS WBC ADHERENCE TO BACTERIA

ALCOHOL’S EFFECT ON THE BODY l CENTRAL NERVOUS SYSTEM 1 dk/hr.02 little change 2 dk/hr.05 drinker high, judgement center of brain affected, inhibitions lowered 3 dk/hr.10 judgement is nil, muscle coordination depressed, stagger, slur speech

ALCOHOL’S EFFECT ON THE BODY 10 dk/hr0.20 emotions erratic, poor memory 1 pint/hr stuporous, judgement long gone, coordination wiped out, sensory perception almost gone 1.25 pints/hr0.40 coma, brain center which controls heart & lungs partially anesthetized

ALCOHOL’S EFFECT ON THE BODY coma 0.60death

Alcohol dehydrogenase is our primary defense against alcohol, a toxic molecule that compromises the function of our nervous system. The high levels of alcohol dehydrogenase in our liver and stomach detoxify about one drink each hour. The alcohol is converted to acetaldehyde, an even more toxic molecule and the main cause of hangovers! Acetaldehyde in turn is converted to acetate and other molecules that are easily processed by our cells. Breaking Down Alcohol

Alcohol dehydrogenase CH 3 CH 2 OH + 2 NAD  CH 3 CHO + 2 NADH alcohol cofactor aldehyde cofactor (ethanol) (acetaldehyde) Acetaldehyde dehydrogenase 2 CH 3 CHO + H 2 O  CH 3 COOH aldehyde acid (acetaldehyde) (acetic acid or vinegar)

Breaking Down Alcohol Acetaldehyde dehydrogenase 2 CH 3 CHO + H 2 O  CH 3 COOH aldehyde acid (acetaldehyde) (acetic acid or vinegar) The acetic acid can be used to form fatty acids (watch that waistline!), or it can be further broken down into CO 2 and water. Via TCA

Alcohol dehydrogenase provides a line of defense against a common toxin in our environment. But alcohol dehydrogenase also modifies other alcohols, sometimes producing even more dangerous products: Methanol, which is commonly used to “denature” ethanol rendering it undrinkable, is converted to formaldehyde by alcohol dehydrogenase. The formaldehyde then causes severe damage, attacking proteins and embalming (denaturing) them. Small amounts of methanol cause blindness, as the sensitive proteins in the retina are attacked, and larger amounts, perhaps a glassful, lead to widespread damage and death. Dangers of Alcohol

There have been studies showing that ADH may have an influence on the dependence on ethanol metabolism in alcoholics. Researchers have tentatively detected a few genes to be associated with alcoholism. If the variants of these genes encode slower metabolizing forms of ADH2 and ADH3, there is increased risk of alcoholism. The studies have found that mutations of ADH2 and ADH3 are related to alcoholism in Northeast Asian populations ethanol metabolism

Breaking Down Methanol Alcohol dehydrogenase CH 3 OH + 2 NAD  CH 2 O + 2 NADH alcohol cofactor aldehyde cofactor (methanol) (formaldehyde) Alcohol dehydrogenase CH 3 CH 2 OH + 2 NAD  CH 3 CHO + 2 NADH alcohol cofactor aldehyde cofactor (ethanol) (acetaldehyde)

Our bodies create at least nine different forms of alcohol dehydrogenase, each with slightly different properties. Most of these are found primarily in the liver, including the  3 form The  form is found in the lining of the stomach. Each enzyme is composed of two subunits. Ethanol is not the only target or substrate of these enzymes, they also make important modifications to retinol, steroids, and fatty acids. Structure (Form) & Function

Human alcohol dehydrogenases use two “helpers” to perform their reaction on ethanol. The first are zinc ions (Zn ++ ), which are used to hold and position the alcohol group on ethanol. The second is the NAD cofactor (constructed using the vitamin niacin), which actually performs the chemical reaction. The zinc atom, shown in light blue, is cradled by three amino acids from the protein: cysteine 46 to the left, cysteine 174 to the right, and histidine 67 above. The ethanol, shown in green and magenta, binds to the zinc and is positioned next to the NAD cofactor, which extends below the ethanol molecule in this illustration. Structure (Form) & Function

Drink responsibly Do Not Drink and Drive Thank you