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high NADH/NAD+ ratio shifts the lactate dehydrogenase equilibrium to lactate, so that pyruvate formed

from alanine is converted to lactate and cannot enter gluconeogenesis. The high NADH/NAD+ ratio also

prevents other major gluconeogenic precursors, such as oxaloacetate and glycerol, from entering the

gluconeogenic pathway.

In contrast, ethanol consumption with a meal may result in a transient hyperglycemia, possibly

because the high NADH/NAD+ ratio inhibits glycolysis at the glyceraldehyde 3-phosphate dehydrogenase

step.

B. Acetaldehyde Toxicity

Many of the toxic effects of chronic ethanol consumption result from accumulation of acetaldehyde, which

is produced from ethanol by both alcohol dehydrogenases and the MEOS. Acetaldehyde accumulates inthe liver and is released into the blood after heavy doses of ethanol (Fig. 33.7). It is highly reactive and

binds covalently to amino groups, sulfhydryl groups, nucleotides, and phospholipids to form “adducts.”

1. Acetaldehyde and Alcohol-Induced Hepatitis

One of the results of acetaldehyde-adduct formation with amino acids is a general decrease in hepatic

protein synthesis (see Fig. 33.7, circle 1). Calmodulin, ribonuclease, and tubulin are some of the proteins

affected. Proteins in the heart and other tissues also may be affected by acetaldehyde that appears in the

blood.

As a consequence of forming acetaldehyde adducts of tubulin, there is a diminished secretion of serum

proteins and VLDLfrom the liver. The liver synthesizes many blood proteins, including serum albumin,

blood coagulation factors, and transport proteins for vitamins, steroids, and iron. These proteins

accumulate in the liver, together with lipid. The accumulation of proteins results in an influx of water (see

Fig. 33.7, circle 6) within the hepatocytes and a swelling of the liver that contributes to portal

hypertension and a disruption of hepatic architecture. 2. Acetaldehyde and Free-Radical Damage

Acetaldehyde-adduct formation enhances free-radical damage. Acetaldehyde binds directly to glutathione

and diminishes its ability to protect against H2O2 and prevent lipid peroxidation (see Fig. 33.7, circle 2).

It also binds to free-radical defense enzymes.

Damage to mitochondria from acetaldehyde and free radicals perpetuates a cycle of toxicity (see Fig.

33.7, circles 3 and 4). With chronic consumption of ethanol, mitochondria become damaged, the rate ofelectron transport is inhibited, and oxidative phosphorylation tends to become uncoupled. Fatty acid

oxidation is decreased even further, thereby enhancing lipid accumulation (see Fig. 33.7, circle 5). The

mitochondrial changes further impair mitochondrial acetaldehyde oxidation, thereby initiating a cycle of

progressively increasing acetaldehyde damage.

The noncaloric effect of heavy and chronic ethanol ingestion that led Ivan A. to believe

ethanol has no calories may be partly attributable to uncoupling of oxidative phosphorylation. The hepatic mitochondria from tissues of chronic alcoholics may be partially

uncoupled and unable to maintain the transmembrane proton gradient necessary for normal rates of

ATP synthesis. Consequently, a greater proportion of the energy in ethanol is converted to heat.

Metabolic disturbances such as the loss of ketone bodies in urine, or futile cycling

of glucose, also

might contribute to a diminished energy value for ethanol. C. Ethanol and Free-Radical Formation

Increased oxidative stress in the liver during chronic ethanol intoxication arises from increased

production of free radicals, principally by CYP2E1. Flavin adenine dinucleotide (FAD) and flavin

mononucleotide (FMN) in the reductase and heme in the cytochrome P450 system transfer single

electrons, thus operating through a mechanism that can generate free radicals. The hydroxyethyl radical

(CH3CH2O•) is produced during ethanol metabolism and can be released as a free radical. Induction of

CYP2E1, as well as other cytochrome P450 enzymes, can increase the generation of free radicals from

drug metabolism and from the activation of toxins and carcinogens (see Fig. 33.7, circle 3). These effects

are enhanced by acetaldehyde-adduct damage.

Phospholipids, the major lipid in cellular membranes, are a primary target of peroxidation caused by

free-radical release. Peroxidation of lipids in the inner mitochondrial membrane may contribute to the

inhibition of electron transport and uncoupling of mitochondria, leading to inflammation and cellular

necrosis. Induction of CYP2E1 and other P450 cytochromes also increases formation of other radicals

and the activation of hepatocarcinogens.

Because of the possibility of mild alcoholic hepatitis and perhaps chronic alcohol-induced

cirrhosis, the physician ordered liver function studies on Jean T. The tests indicated an

ALT level of 46 U/L (reference range, 5 to 30 U/L) and an AST level of 98 U/L (reference range,

10 to 30 U/L). The concentration of these enzymes is high in hepatocytes. When hepatocellular

membranes are damaged in any way, these enzymes are released into the blood. Jean’s serum

alkaline phosphatase level was 195 U/L (reference range, 56 to 155 U/L for an adult female). The

serum total bilirubin level was 2.4 mg/dL (reference range, 0.2 to 1.0 mg/L). These tests show

impaired capacity for normal liver function. Her blood hemoglobin and hematocrit levels were

slightly below the normal range, consistent with a toxic effect of ethanol on red blood cell

production by bone marrow. Serum folate and vitamin B12 levels were also slightly suppressed.

Folate is dependent on the liver for its activation and recovery from the enterohepatic circulation.Vitamin B12 is dependent on the liver for synthesis of its blood carrier proteins. Thus, Jean T.

shows many of the consequences of hepatic damage. D. Hepatic Cirrhosis and Loss of Liver Function

Liver injury is irreversible at the stage that hepatic cirrhosis develops. Initially, the liver may be

enlarged, full of fat, and crossed with collagen fibers (fibrosis) and may have nodules of regenerating

hepatocytes ballooning between the fibers. As liver function is lost, the liver becomes shrunken (Laennec

cirrhosis). During the development of cirrhosis, many of the normal metabolic functions of the liver are

lost, including biosynthetic and detoxification pathways. Synthesis of blood proteins, including blood

coagulation factors and serum albumin, is decreased. The capacity to incorporate amino groups into urea

is decreased, resulting in the accumulation of toxic levels of ammonia in the blood.

Conjugation and

excretion of the yellow pigment bilirubin (a product of heme degradation) is diminished, and bilirubin

accumulates in the blood. It is deposited in many tissues, including the skin and sclerae of the eyes,

causing the patient to become visibly yellow. Such a patient is said to be jaundiced.

CLINICAL COM M ENTS

When ethanol consumption is low (<15% of the calories in the diet), it is used efficiently to

produce ATP, thereby contributing to Ivan A.’s weight gain. However, in individuals with chronic

consumption of large amounts of ethanol, the caloric content of ethanol is not converted to ATP as

effectively. Some of the factors that may contribute to this decreased efficiency include mitochondrial

damage (inhibition of oxidative phosphorylation and uncoupling) resulting in the loss of calories as heat,

increased recycling of metabolites such as ketone bodies, and inhibition of the normal pathways of fatty

acid and glucose oxidation. In addition, heavier drinkers metabolize an increased amount of alcohol

through the MEOS, which generates less ATP.

Al M. Al M. was suffering from acute effects of high ethanol ingestion in the absence of food

intake. Both heavy ethanol consumption and low caloric intake increase adipose tissue lipolysis

and elevate blood fatty acids. As a consequence of his elevated hepatic NADH/NAD+ ratio, acetyl-CoA

produced from fatty acid oxidation was diverted from the TCA cycle into the pathway of ketone-body

synthesis. Because his skeletal muscles were using acetate as a fuel, ketone-body use was diminished,

resulting in ketoacidosis. Al’s moderately low blood glucose level also suggests that his high hepatic

NADH level prevented pyruvate and glycerol from entering the gluconeogenic pathway. Pyruvate is

diverted to lactate, which may have contributed to his metabolic acidosis and anion gap, along with the

ketone bodies.

Rehydration with intravenous fluids containing glucose, thiamin, and potassium was initiated. Al’s

initial potassium level was low, possibly secondary to vomiting. Thiamin is given in case there is thiamin

deficiency. An orthopedic surgeon was consulted regarding the compound fracture of his right forearm.

Jean T. Jean T.’s signs and symptoms, as well as her laboratory profile, were consistent with the

presence of mild reversible alcohol-induced hepatocellular inflammation (alcohol-induced

hepatitis) superimposed on a degree of irreversible scarring of liver tissues, known as chronic alcoholic(Laennec) cirrhosis of the liver. The chronic inflammatory process associated with long-term ethanol

abuse in patients such as Jean T. is accompanied by increases in the levels of serum alanine

aminotransferase (ALT) and aspartate aminotransferase (AST). Her elevated bilirubin and alkaline

phosphatase levels in the blood were consistent with hepatic damage. Her values for ALT and AST were

significantly below those seen in acute viral hepatitis. In addition, the ratio of the absolute values for

serum ALT and AST often differ in the two diseases, tending to be >1 in acute viral hepatitis and <1 in

chronic alcohol-induced cirrhosis. The reason for the difference in ratio of enzyme activities released is

not fully understood, but a lower level of ALT in the serum may be attributable to an alcohol-induced

deficiency of pyridoxal phosphate. In addition, serologic tests for viral hepatitis were nonreactive. Her

serum folate and vitamin B12 were also slightly suppressed, indicating impaired nutritional status.

Jean was strongly cautioned to abstain from alcohol immediately and to improve her nutritional status.

In addition, she was referred to the hospital drug and alcohol rehabilitation unit for appropriate

psychological therapy and supportive social counseling. The physician also arranged for a follow-up

office visit in 2 weeks.

In liver fibrosis, disruption of the normal liver architecture, including sinusoids, impairs

blood from the portal vein. Increased portal vein pressure (portal hypertension) causes

capillaries to anastomose (to meet and unite or run into each other) and form thin-walled dilated

esophageal venous conduits known as esophageal varices. When these burst, there is hemorrhaging into the GI tract. The bleeding can be very profuse because of the high venous

pressure within these varices in addition to the adverse effect of impaired hepatic function on the

production of blood-clotting proteins. B IOCHEM ICAL COM M ENTS

Fibrosis in Chronic Alcohol-Induced Liver Disease. Fibrosis is the excessive accumulation of

connective tissue in parenchymal organs. In the liver, it is a frequent event following a repeated or

chronic insult of sufficient intensity (such as chronic ethanol intoxication or infection by a hepatitis virus)

to trigger a “wound healing–like” reaction. Regardless of the insult, the events are similar: An

overproduction of extracellular matrix components occurs, with the tendency to progress to sclerosis,

accompanied by a degenerative alteration in the composition of matrix components (Table 33.2). Some

individuals (<20% of those who chronically consume alcohol) go on to develop cirrhosis.Although the full spectrum of alcohol-induced liver disease may be present in a wellnourished individual, the presence of nutritional deficiencies enhances the progression of

the disease. Ethanol creates nutritional deficiencies in several different ways. The ingestion of

ethanol reduces the GI absorption of foods that contain essential nutrients, including vitamins,

essential fatty acids, and essential amino acids. For example, ethanol interferes with absorption of

folate, thiamin, and other nutrients. Secondary malabsorption can occur through GI complications,

pancreatic insufficiency, and impaired hepatic metabolism or impaired hepatic storage of nutrients

such as vitamin A. Changes in the level of transport proteins produced by the liver also strongly

affect nutrient status.

The development of hepatic fibrosis after ethanol consumption is related to stimulation of the

mitogenic development of stellate (Ito) cells into myofibroblasts, and stimulation of the production of

collagen type I and fibronectin by these cells. The stellate cells are perisinusoidal cells lodged in the

space of Disse that produce extracellular matrix protein. Normally, the space of Disse contains basement

membrane–like collagen (collagen type IV) and laminin. As the stellate cells are activated, they change

from a resting cell filled with lipids and vitamin A to one that proliferates, loses its vitamin A content,

and secretes large quantities of extracellular matrix components.

One of the initial events in the activation and proliferation of stellate cells is the activation of Kupffer

cells, which are macrophages that reside in the liver sinusoids (Fig. 33.8). The Kupffer cells are probably

activated by a product of the damaged hepatocytes, such as necrotic debris, iron, reactive oxygen species

(ROS), acetaldehyde, or aldehyde products of lipid peroxidation. Kupffer cells also may produce

acetaldehyde from ethanol internally through their own MEOS pathway.Activated Kupffer cells produce several products that contribute to activation of stellate cells. They

generate additional ROS through NADPH oxidase during the oxidative burst and reactive nitrogen–

oxygen species (RNOS) through inducible nitric oxide (NO) synthase (see Chapter 25). In addition, they

secrete an impressive array of growth factors, such as cytokines, chemokines, prostaglandins, and other

reactive molecules. The cytokine transforming growth factor β1 (TGF-β1), produced by both Kupffer cells

and sinusoidal endothelial cells, is a major player in the activation of stellate cells. Once they are

activated, the stellate cells produce collagen and proteases, leading to an enhanced fibrotic network

within the liver. Stellate cells may also be partially activated by hepatocyte release of ROS and

acetaldehyde directly, with the involvement of Kupffer cells.

Recent evidence also indicates that chronic alcohol usage can disrupt gene regulation within the liver,

through modification of the activity of sirtuin1 (see “Biochemical Comments” in Chapter 30). Sirtuin 1

(SIRT-1) is a histone deacetylase that uses NAD+ as a substrate (see Fig. 30.21), producing nicotinamide

and acetyl-ADP-ribose. Deacylation of appropriate targets leads to alterations in gene expression.

Ethanol will lead to a downregulation of SIRT-1 activity. Ethanol may lead to reduced SIRT-1 activity

through an increase in the NADH/NAD+ ratio in the liver, thereby reducing the level of substrate (NAD+)

required for SIRT-1 activity.

Interestingly, it also appears that a reduction in SIRT-1 activity leads to a reduction in AMP-activated

protein kinase activity (AMPK). Under normal conditions, SIRT-1 deacetylates LBK1, activating it,

which phosphorylates and activates the AMPK. AMPK (see “Biochemical Comments” in Chapter 34)

phosphorylates and inhibits acetyl-CoA carboxylase, resulting in reduced production of malonyl

coenzyme A (malonyl-CoA). Malonyl-CoA is an inhibitor of carnitine palmitoyltransferase I (CPTI), so

reduced levels of malonyl-CoA lead to increased activity of CPTI and increased levels of fatty acid

oxidation. Ethanol-induced inhibition of SIRT-1 will lead to inhibition of hepatic AMPK (because of

LBK1 remaining inactive), thereby activating acetyl-CoA carboxylase, producing malonyl-CoA, and

blocking fatty acid oxidation in the liver. This will result in the fatty acid and triglyceride synthesis in the

liver, leading to the development of alcoholic fatty liver disease.

KEY CONCEPTSEthanol metabolism occurs primarily in the liver, via a two-step oxidation sequence to acetate plus

NADH.

Acetate is activated to acetyl-CoA for energy generation by most tissues of the

body.

The ALD family of enzymes catalyzes the first step of alcohol oxidation. The ALDH family of

enzymes catalyzes the second step of the pathway.

When ethanol levels are high, the microsomal ethanol-oxidizing system (MEOS), consisting of

CYP2E1, is induced.

Acute effects of ethanol ingestion are caused by the elevated NADH/NAD+ ratio, which leads to

Inhibition of fatty acid oxidation Ketogenesis

Hyperlipidemia

Inhibition of gluconeogenesis Lactic acidosis Hyperuricemia

Chronic effects of ethanol ingestion include

Hepatic steatosis (fatty acid accumulation within the liver) Hepatitis

Fibrosis (excessive collagen production within the liver) Cirrhosis (eventual liver death)

The chronic effects of ethanol are caused by acetaldehyde and ROS production during ethanol

metabolism.

The diseases discussed in this chapter are summarized in Table 33.3. REVIEW QUESTIONS—CHAPTER 33

1.The fate of acetate, the product of ethanol metabolism, is which one of the following?

A. It is taken up by other tissues and activated to acetyl-CoA.B. It is toxic to the tissues of the body and can lead to hepatic necrosis.

C. It is excreted in bile.

D. It enters the TCA cycle directly to be oxidized. E. It is converted into NADH by ADH.

2.Which one of the following would be expected to occur after acute alcohol ingestion?

A. Activation of fatty acid oxidation B. Lactic acidosis

C. Inhibition of ketogenesis

D. An increase in the NAD+/NADH ratio E. An increase in gluconeogenesis

3.A chronic alcoholic is in treatment for alcohol abuse. The drug disulfiram is prescribed for the

patient. This drug deters the consumption of alcohol by which one of the following mechanisms?

A. Inhibiting the absorption of ethanol so that an individual cannot become intoxicated, regardless of

how much he or she drinks

B. Inhibiting the conversion of ethanol to acetaldehyde, which cause the excretion of unmetabolized

ethanol

C. Blocking the conversion of acetaldehyde to acetate, which causes the accumulation of

acetaldehyde

D. Activating the excessive metabolism of ethanol to acetate, which causes inebriation with

consumption of a small amount of alcohol

E. Preventing the excretion of acetate, which causes nausea and vomiting

4.Induction of CYP2E1 would result in which of the following?

A.A decreased clearance of ethanol from the blood

B.A decrease in the rate of acetaldehyde production

C.A low possibility of the generation of free radicals

D.Protection from hepatic damage

E.An increase of one’s alcohol tolerance level

5. Which one of the following consequences of chronic alcohol consumption is irreversible?

A. Inhibition of fatty acid oxidation

B.Activation of triacylglycerol synthesis

C.Ketoacidosis

D.Lactic acidosis

E.Liver cirrhosis

6. A chronic alcoholic, on a binge, is severely hypoglycemic. Under these conditions, gluconeogenic

precursors are trapped and cannot progress to form glucose. Which one of the following is such a

trapped intermediate?

A.Glycerol

B.Dihydroxyacetone phosphate

C.Glyceraldehyde 3-phosphate

D.Glycerol 3-phosphate

E.Pyruvate7. Your patient is a chronic alcoholic who is frequently malnourished and is exhibiting symptoms of a

vitamin deficiency because of chronic alcohol consumption. This patient would most likely have

trouble catalyzing which one of the following reactions because of the vitamin deficiency?

A.Sedoheptulose 7-phosphate + glyceraldehyde 3-phosphate → erythrose 4-phosphate + fructose

6-phosphate

B.Ribose 5-phosphate + xylulose 5-phosphate → sedoheptulose 7-phosphate + glyceraldehyde 3-

phosphate

C.Glucose 6-phosphate + 2 NADP+ → CO2 + ribulose 5-phosphate + 2 NADPH

D.Isocitrate + NAD+ → CO2 + α-ketoglutarate + NADH

E.Oxaloacetate + guanosine triphosphate → phosphoenolpyruvate + CO2 + guanosine diphosphate

8. The enzymes that metabolize ethanol exist as a variety of isozymes in the general population. A

slow-activity isozyme of which enzyme is most likely responsible for an individual to exhibit a very

low tolerance to alcohol, leading to the individual rarely drinking?

A.Acetyl-CoA synthetase

B.MEOS

C.Acetyl-CoA carboxylase

D.ADH

E.ALDH

9. What would be an outcome if a person had a defect in which the metabolites of ethanol could not

enter the mitochondria?

A.Acetate would accumulate, which is toxic.

B.Acetaldehyde would accumulate, which is toxic.

C.Acetate would be activated by tissues to acetyl-CoA.

D.Acetaldehyde would be activated by tissues to acetyl-CoA.

E.The MEOS would not function.

10. The possibility of ROS being generated during ethanol metabolism occurs via which one of the

following enzyme systems?

A.MEOS

B.ADH

C.ALDH

D.Acetyl-CoA Synthetase

E.Citrate synthase ANSWERS TO REVIEW QUESTIONS

1. The answer is A. Acetate is converted to acetyl-CoA by other tissues so that it can enter the TCA

cycle to generate ATP. Answer B is incorrect because acetaldehyde, not acetate, is toxic to cells.

Answer C is incorrect because acetate is excreted by the lung and kidney and not in the bile.

Answer D is incorrect because acetate cannot enter the TCA cycle directly. It must be converted to

acetyl-CoA first. Answer E is incorrect because alcohol dehydrogenase converts

ethanol into

acetaldehyde. It does not convert acetate into NADH.2. The answer is B. There is an increase in the NADH/ NAD+ ratio because NADH is produced by

the conversion of ethanol to acetate (thus, D is incorrect). The increased ratio of NADH/NAD+

favors the conversion of gluconeogenic precursors (such as pyruvate and oxaloacetate) to their

reduced counterparts (lactate and malate, respectively) in order to generate NAD+ for ethanol

metabolism. This reduces the concentration of gluconeogenic precursors and slows down

gluconeogenesis (thus, E is incorrect) and can lead to lactic acidosis. Answer A is incorrect

because the increase of NADH inhibits fatty acid oxidation. Answer C is incorrect because

ketogenesis increases as a result of the increase of NADH and acetyl-CoA in the mitochondria.

NADH inhibits key enzymes of the TCA cycle, thereby diverting acetyl-CoA from the TCA cycle

and toward ketone-body synthesis.

3.The answer is C. Disulfiram blocks the conversion of acetaldehyde to acetate (the reaction

catalyzed by ALDH). The accumulation of acetaldehyde is toxic and causes vomiting and nausea.

Answers A and B are incorrect because disulfiram would not interfere with the absorption of

ethanol or the first step of its metabolism. Answer D is incorrect because an ALDH inhibitor

(such as disulfiram) would inhibit the conversion of ethanol to acetate, not increase the rate of the

conversion. Answer E is incorrect because disulfiram does not interfere with the excretion of

acetate, nor does acetate accumulation lead to nausea and vomiting.

4.The answer is E. An increase in the concentration of CYP2E1 (the MEOS system) would result in

an increase of ethanol metabolism and clearance from the blood (thus, A is incorrect). An

increased rate of acetaldehyde production would result (thus, B is incorrect). The increase in

CYP2E1 would cause an increase in the probability of producing free radicals (thus, C is

incorrect). Answer D is incorrect because hepatic damage would be more likely to occur because

there is an increase of free-radical production. Answer E is correct because the increased

clearance rate of ethanol from the blood results in a higher alcohol tolerance level.

5.The answer is E. Liver cirrhosis is irreversible. It is an end-stage process of liver fibrosis.

Answers A, B, C, and D are all consequences of liver disease, but they are all reversible.

Therefore, E is the only answer that is correct.

6.The answer is D. The gluconeogenic precursors are lactate, glycerol, and amino acids (primarily

alanine) from muscle protein degradation. Under the conditions of high alcohol intake for extended

periods, the NADH/NAD+ ratio is very high owing to alcohol being converted to acetaldehyde

and then acetic acid. Gluconeogenesis is impaired because of the high levels of NADH present.

Lactate cannot be converted to pyruvate (the reaction requires NAD+, which is present in very

low levels). Alanine can be converted to pyruvate, which is converted to oxaloacetate via

pyruvate carboxylase, but the oxaloacetate is trapped and cannot be converted to

malate owing to

the low NAD+ levels as well. Glycerol metabolism requires first, phosphorylation to glycerol 3-P,

and then oxidation of carbon 2 to form dihydroxyacetone phosphate, an NAD+-requiring reaction.

Thus, when NAD+ levels are low, glycerol 3-P, lactate, and oxaloacetate will all be trapped and

cannot efficiently progress through the gluconeogenic pathway.

7.The answer is B. The patient is likely to be thiamin-deficient, which is a required factor for

oxidative decarboxylation reactions (pyruvate dehydrogenase and α-ketoglutarate dehydrogenase)

and transketolase. Ethanol interferes with the absorption of thiamin from the digestive tract. Thereaction of ribose 5-phosphate with xylulose 5-phosphate to produce sedoheptulose 7-phosphate

and glyceraldehyde 3-phosphate is catalyzed by transketolase. The conversion of sedoheptulose 7-

phosphate and glyceraldehyde 3-phosphate to erythrose 4-phosphate and fructose 6-phosphate is a

three-carbon transfer catalyzed by transaldolase, which does not require an exogenous vitamin for

activity. The conversion of glucose 6-phosphate to ribulose 5-phosphate is catalyzed by glucose

6-phosphate dehydrogenase, which requires niacin as a cofactor but not thiamin. Isocitrate

dehydrogenase, which requires niacin (but not thiamin), catalyzes the conversion of isocitrate to

α-ketoglutarate. Phosphoenolpyruvate (PEP) carboxykinase catalyzes the conversion of oxaloacetate to PEP and does not require a vitamin cofactor.

8.The answer is E. An isozyme of ALDH has a dramatically increased Km (>200-fold) and a 10-

fold reduced V

max. In such individuals, acetaldehyde, the toxic component of alcohol ingestion, accumulates to a large extent, leading to the individual having a very low tolerance for alcohol. A

slow-acting ADH would not lead to a low tolerance to alcohol because acetaldehyde accumulation (the toxic intermediate of alcohol metabolism) would be slowed such that the

acetaldehyde produced can be safely metabolized without any side effects. Acetate, once

produced, is not toxic, so a slow-acting acetyl-CoA synthetase (which uses acetate as a substrate)

would not lead to the accumulation of a toxic intermediate. MEOS is used as an alternative

ethanol-oxidizing system when ethanol levels are high. A slow-acting MEOS would reduce the

production of acetaldehyde, which is the toxic intermediate of alcohol metabolism. This would not

lead to a low level of tolerance to alcohol. Acetyl-CoA carboxylase is not involved in ethanol

metabolism (the acetyl-CoA formed would be used for energy). Acetyl-CoA carboxylase is

needed for fatty acid synthesis, and if its activity were low, fatty acid production would be

reduced, but it would have no effect on the tolerance to alcohol.

9.The answer is B. The main route for metabolism of ethanol is through ADH in the cytosol

producing acetaldehyde, which is the toxic intermediate of alcohol metabolism. Acetaldehyde is

further oxidized in mitochondria to acetate, which is then activated by tissues to acetyl-CoA,

which is oxidized in the TCA cycle. If entry of acetaldehyde into the mitochondria is blocked, then

acetaldehyde accumulates and acetate is not formed. The MEOS is in the endoplasmic reticulum

(cytosolic) and would continue to produce acetaldehyde and NADP+.

10. The answer is A. The MEOS is induced by ethanol and uses a cytochrome P450 system to oxidize

ethanol. The cytochrome P450 enzyme systems transfer a single electron at a time through an iron

within a heme group in the cytochrome, and this is the step at which the electron may escape and

convert oxygen to superoxide, thereby generating ROS. ADH and ALDH transfer hydride ions to

NAD+, and there is a very low probability of electrons escaping from those oxidation–reduction

reactions. Acetyl-CoA synthetase does not catalyze an oxidation–reduction reaction (it catalyzes

the conversion of acetate to acetyl-CoA), nor does citrate synthase (the formation of citrate from

acetyl-CoA and oxaloacetate). The possibility of losing an electron during a reaction in which

electrons are not being transferred is very low.Integration of Carbohydrate and Lipid

Metabolism 34

For additional ancillary materials related to this chapter, please visit thePoint. This chapter summarizes and integrates the major pathways for the use of carbohydrates and fats as fuels.

We concentrate on reviewing the regulatory mechanisms that determine the flux of metabolites in the fed

and fasting states, integrating the pathways that were described separately under carbohydrate and lipid

metabolism. The next section of the book covers the mechanisms by which the pathways of nitrogen

metabolism are coordinated with fat and carbohydrate metabolism.

For the species to survive, it is necessary for us to store excess food when we eat and to use these

stores when we are fasting. Regulatory mechanisms direct compounds through the pathways of

metabolism involved in the storage and use of fuels. These mechanisms are controlled by hormones, by

the concentration of available fuels, and by the energy needs of the body.

Changes in hormone levels, in the concentration of fuels, and in energy requirements affect the activity

of key enzymes in the major pathways of metabolism. Intracellular enzymes are generally regulated by

activation and inhibition, by phosphorylation and dephosphorylation (or other covalent modifications),

by induction and repression of synthesis, and by degradation. Activation and inhibition of enzymes

cause immediate changes in metabolism. Phosphorylation and dephosphorylation of enzymes affect

metabolism slightly less rapidly. Induction and repression of enzyme synthesis are much slower

processes, usually affecting metabolic flux over a period of hours. Degradation of enzymes decreases the

amount available to catalyze reactions.

The pathways of metabolism have multiple control points and multiple regulators at each control

point. The function of these complex mechanisms is to produce a graded response to a stimulus and to

provide sensitivity to multiple stimuli so that an exact balance is maintained between flux through a given

step (or series of steps) and the need or use for the product. Pyruvate dehydrogenase (PDH) is an example

of an enzyme that has multiple regulatory mechanisms. Regardless of insulin levels, the enzyme cannotbecome fully activated in the presence of products and absence of substrates.

The major hormones that regulate the pathways of fuel metabolism are insulin and glucagon. In liver,