Understanding Alcohol Metabolism

Beers and wines contain ethanol (CH3CH2OH) that gives people horrifying hangover sometimes. Ethanol is fast absorbed throughout the whole gastrointestinal tract, transported unaltered in the bloodstream, and then degraded in tissues (mainly liver).

Here is a scheme pictures of the ethanol metabolism in the hepatic cells (Figure 1).

Figure 1.

Enzymes involved are:
ADH-Alcohol dehydrogenase
ALDH2-Aldehyde dehydrogenase 2
Catalase (in the presence of hydrogen peroxide)

Figure 1 shows two pathways of ethanol metabolism: alcohol dehydrogenase pathway (ADH) and the microsonal ethanol oxidizing (MEO) pathyway.
1. ADH Pathyway

Figure 2.

This is the main pathway that ethanol oxidation follows. The toxic level of blood ethanol is 50-100 mg/dL, while the ADH enzyme itself is easily saturated when the blood ethanol reaches 15 mg/dL (3 times more than Km=5mg/dL). Where do those excessive alcohol metabolize? Follow me.

2. MEO Pathway
Figure 3.

Oxidation for excessive ethanol happens in the microsome through electron transport, thus this process is also called the microsomal electron transport system.

The system consists of substrate NADPH and O2, electron transporters FAD, FADH2, FMNH2, FMN, and cytochrome P-450. Therefore, the redox-reactions happen here are similar to mitochondria electron transport chain. NADPH is firstly oxidized by O2 and generates NADP+, which then oxidizes the ethanol to acetaldehyde and water.

Why can alcoholics drink enormously before getting hammered?
Due to the cytochrome P-450. Excessive ethanol induce synthesis of the cytochrome P-450, thus establish higher metabolic efficiency towards ethanol. This is why alcoholic can drink very large quantities before showing alcohol intoxication.

So alcohol can be oxidized and even metabolic tolerated. Then why don't doctors approve of alcoholism? Here is the answer:
1. Fatty liver and lactic acidosis
ADH pathway produces NADH, but exhausts the NAD+ pool. The increased NADH:NAD+ ratio directs metabolism away from Kreb cycle and toward fatty acid synthesis.

Pyruvate is the end product of Glycolysis. Under aerobic condition, pyruvate is converted to Acetyl-CoA, which then enter Kreb cycle for ATP production. The whole Kreb cycle relies on an important cosubstrate--NAD+.

However, NAD+ pool was exhausted by through the ADH pathway. Low [NAD+] hinders and compromises Kreb cycle by slowing dehydrogenase activity in the Kreb cycle and accumulating citrate and pyruvate.

Figure 4.

What happens to the accumulated pyruvate?
Pyruvate, NADH, and H+ are catalyzed by lactate dehydrogenase to form lactate and NAD+ (The reaction is driven by the massive NADH). High blood lactate level contributes to the lactic acidosis.

What happens to the accumulated citrate?
Citrate is directed to synthesis of Acetyl CoA (Figure 5), which will synthesis Malonyl CoA and together enter fatty acid synthesis (Figure 6). Therefore, the accumulated citrate in the Kreb cycle leads to fatty acid deposits in the hepatic cell and thus results in fatty liver.

Figure 5.

Figure 6.


















How do people feel in the case of low ATP production and high blood lactic acid?
Ethanol metabolism interferes with the energy production in Kreb cycle. This might be the reason of feeling dizzy, tired, and muscle soreness.

2. Cirrhosis
Cirrhosis is initiated by the fibrosis of the liver, due to acetaldehyde overproduction (by ADH and MEO pathway, Figure 2, 3 ). Acetaldehyde impedes the formation of microtubules in hepatic cells and causes the development of perivenular fibrosis. In addition, acetaldehyde binds proteins and form adduct, therefore impairs the protein/enzyme functions.

3. Vitamin malabsorption

4. Reactive oxygen species (ROS) production
As Figure 1 shown, hydrogen peroxide (H2O2) is produced and neutralized to H2O by catalase. However, when H2O2 is overloaded and antioxidant defense (e.g. glutathione, catalase, and vitamins) is not sufficient, the oxidative stress is increased.

Another source of ROS might be the microsome electron transport system, which produces superoxide (O2-).

The ROS production in the ethanol metabolism is closely related to my current study on oxidative stress and endothelial function. We tend to exclude subjects who drink alcohol regularly. Alcohol consumption abivously increases oxidative stress, in particular, lipid peroxidation (Figure 7), even though antioxidant capacity may be evolved overtime in alcoholics.

Figure 7.