Biochemistry digestion

What happens to CYP2E1 levels in chronic alcoholism?

CYP2E1 is upregulated, increasing acetaldehyde and reactive oxygen species production.

How does CYP2E1 contribute to ethanol metabolism?

It catalyzes ethanol oxidation in the MEOS, generating acetaldehyde and free radicals.

What chemical groups does acetaldehyde bind to on biomolecules?

Amino (–NH₂) groups, sulfhydryl (–SH) groups, nucleic acids, and phospholipids.

What is the consequence of acetaldehyde–protein adduct formation?

Nonfunctional complexes form, impairing protein activity, antioxidant defense, and exocytosis.

How do acetaldehyde adducts affect hepatocyte antioxidant defenses?

They inactivate glutathione-related enzymes and other ROS scavengers.

What happens to hepatocyte protein secretion in alcoholism?

Secretion of albumin, coagulation factors, transport proteins, and LDL decreases.

Why do hepatocytes swell in alcoholic liver injury?

Intracellular accumulation of undegraded proteins raises osmotic pressure, drawing in water.

How does widespread hepatocyte swelling lead to portal hypertension?

Enlarged hepatocytes compress sinusoids and portal veins, raising resistance to blood flow.

What role do free radicals play in alcoholic liver damage?

ROS from CYP2E1 cause lipid peroxidation, membrane damage, and mitochondrial dysfunction.

How does oxidative phosphorylation change in alcoholic liver injury?

It weakens due to mitochondrial damage, reducing ATP production.

What sequence leads from hepatocyte necrosis to cirrhosis?

Necrosis → stellate-cell activation → collagen deposition (fibrosis) → regenerative nodule formation (cirrhosis).

What characterizes alcoholic fatty liver (steatosis)?

Triglyceride accumulation in hepatocytes, producing a pale, enlarged liver.

Can alcoholic fatty liver be reversed?

Yes—abstinence allows hepatocytes to clear fat and restore normal architecture.

What marks the transition from reversible to irreversible liver lesions?

Development of significant fibrosis impairs regeneration, leading to cirrhosis.

What is cirrhosis?

End-stage liver disease with diffuse fibrosis and regenerative nodules, causing permanent dysfunction.

Name four WHO-defined liver functions related to detoxification.

Glucose metabolism, excretory (bile pigments/salts), synthetic (albumin/coagulation factors), storage (fat-soluble vitamins).

Define a xenobiotic.

A compound entering the body from outside that is not a nutrient (e.g., food additives, drugs).

Define an autobiotic.

A compound produced within the body (e.g., bilirubin).

What is biotransformation?

The ensemble of biochemical processes converting xenobiotics and autobiotics into forms suitable for elimination.

What is the main goal of Phase I biotransformation reactions?

To introduce or expose functional groups, increasing polarity and reducing toxicity.

Give two examples of Phase I reactions.

Oxidation and reduction.

What is the primary enzyme family mediating Phase I oxidation?

Cytochrome P450 monooxygenases (CYPs).

Where are microsomal CYP enzymes located?

Attached to the endoplasmic reticulum of hepatocytes.

What harmful byproducts can CYP reactions generate?

Free radicals and reactive oxygen species.

How many CYP isoenzymes exist approximately?

About 150 enzymes grouped into 10 families, encoded by 57 genes.

What percentage of drugs are metabolized by CYP monooxygenases?

Approximately 75 %.

Which CYP isoenzyme is most active in ethanol metabolism?

CYP2E1.

Which CYP is most abundant in human liver and metabolizes many drugs?

CYP3A4, accounting for 30–40 % of total CYP activity.

How does grapefruit juice affect CYP3A4?

It can decrease CYP3A4 activity up to 14-fold, slowing statin metabolism and increasing side-effects.

What is the main purpose of Phase II biotransformation?

To conjugate polar groups or methylate metabolites, preparing them for excretion.

List four common Phase II conjugation reactions.

Glucuronidation, sulfation, amino-acid conjugation, glutathione conjugation.

Where do most Phase II reactions occur?

In liver cells.

Through which routes are conjugated metabolites excreted?

Biliary and renal excretion.

What percentage of ingested ethanol does the liver metabolize?

Over 90 %.

Name the three oxidative pathways for ethanol metabolism.

Alcohol dehydrogenase (ADH), MEOS (CYP2E1), and catalase.

What toxic metabolite accumulates during ethanol metabolism?

Acetaldehyde.

Which enzyme converts ethanol to acetaldehyde?

Alcohol dehydrogenase (ADH).

What is the Km range for class I ADH in liver?

Approximately 0.013–4 mM, indicating high ethanol affinity.

What pathway becomes inducible with chronic alcohol intake?

MEOS via upregulation of CYP2E1.

What is the Km for ethanol of CYP2E1?

About 11 mM, indicating lower affinity than ADH.

Which enzyme converts acetaldehyde to acetate?

Aldehyde dehydrogenase (ALDH), mainly mitochondrial ALDH-2.

What is the Km of ALDH-2 for acetaldehyde?

0.2 μM.

How does ALDH polymorphism affect alcohol tolerance?

Reduced ALDH activity (e.g. Km 46 μM) leads to acetaldehyde buildup, causing nausea and vomiting.

What nonoxidative ethanol metabolism reaction can damage the pancreas and liver?

Formation of fatty acid ethyl esters by RR ethyl ester synthase.

Why do women have higher blood alcohol levels than men after equivalent intake?

Lower gastric ADH activity and body composition differences result in less first-pass metabolism.

How does an increased NADH/NAD⁺ ratio affect pyruvate metabolism?

Shifts pyruvate to lactate, causing lactic acidosis.

What effect does NADH overload have on oxaloacetate?

Converts oxaloacetate to malate, depleting it and impairing gluconeogenesis (hypoglycemia).

How does high NADH influence lipid metabolism?

Inhibits fatty acid oxidation, promotes triglyceride synthesis (steatosis) and ketogenesis.

Why does hyperuricemia occur in acute intoxication?

Lactate competes with uric acid for renal excretion, decreasing uric acid clearance.

List four metabolic derangements of acute ethanol intoxication.

Lactic acidosis, hypertriglyceridemia, ketonemia, hypoglycemia.

What are the five simplified WHO functions of the liver in detoxification?

Glucose metabolism, excretory function, synthetic function, storage, and secretion.

What happens to glucose during the feeding phase in the liver?

It is converted into glycogen and stored.

What does the liver do with glucose during fasting?

It breaks down glycogen to release glucose into the blood.

What excretory functions does the liver perform?

Excretion of bile pigments (bilirubin), bile salts (for fat absorption), and other harmful substances.

Which key proteins does the liver synthesize?

Albumin and coagulation factors.

What vitamins are stored in the liver?

Fat-soluble vitamins (A, D, E, K).

What substances are secreted by the liver?

Proteins, enzymes, and lipoproteins.

Name three processes by which the liver maintains glucose homeostasis.

Glycogen synthesis/storage, glycogen decomposition with glucose release, and gluconeogenesis.

How is “excretion” defined in the context of liver detoxification?

Broadly as detoxification and elimination of compounds from the organism.

Define a xenobiotic.

A compound from outside the organism (natural or artificial) that is not a nutrient, e.g., food additives or drugs.

Define an autobiotic.

A compound formed within the body, e.g., bilirubin from heme breakdown.

What is biotransformation?

The total biochemical processes required to detoxify and eliminate xenobiotics and autobiotics (synonymous with metabolism).

What is the goal of Phase I biotransformation reactions?

To reduce toxicity by adding functional groups, increasing polarity and water solubility (via oxidation or reduction).

What is the main purpose of Phase II biotransformation reactions?

To prepare compounds for elimination via conjugation with polar, negatively charged groups or by methylation.

Do all compounds undergo both Phase I and Phase II biotransformation?

No

What is the most common Phase I hydrolysis reaction?

Hydrolysis of xenobiotic esters, such as acetylsalicylic acid (aspirin).

Which enzyme family catalyzes the dominant Phase I oxidation reactions?

Cytochrome P450 monooxygenases (oxidoreductases).

What is the basic action of CYP monooxygenases?

They add one atom of molecular oxygen to substrates, forming more polar metabolites.

Where are microsomal CYP enzymes located?

In the smooth endoplasmic reticulum of hepatocytes.

What harmful byproducts are generated by CYP-catalyzed reactions?

Free radicals and reactive oxygen species (ROS).

Approximately how many CYP isoenzymes exist?

About 150 isoenzymes, grouped into families and subfamilies.

How are CYP genes regulated?

They are inducible by substrates and exhibit genetic polymorphism.

Besides detoxification, in what biosynthetic processes are CYP enzymes involved?

Synthesis of primary bile acids and steroid hormones.

How many CYP genes have been characterized?

Fifty-seven genes encoding about 150 enzymes in 10 families.

How are CYP genes and enzymes named?

“CYP” + family number + subfamily letter + individual gene number (e.g., CYP3A4).

What percentage of drugs are metabolized by CYP monooxygenases?

Approximately 75 %.

Which CYP isoenzyme is most active in ethanol metabolism?

CYP2E1.

Which human liver CYP metabolizes 30–40 % of drugs and is inhibited by grapefruit juice?

CYP3A4.

How does grapefruit juice affect CYP3A4 activity?

It can decrease CYP3A4 activity up to 14-fold, slowing statin metabolism and increasing side effects.

What conjugation reactions occur in Phase II metabolism?

Glucuronidation, sulfation, amino-acid conjugation, glutathione conjugation, and methylation.

Where do most Phase II reactions take place?

In liver cells.

How are Phase II conjugates excreted?

Via the biliary route or the renal route.

What fraction of ingested ethanol is absorbed in the upper digestive tract?

About 5 %.

Where is the remainder of ingested ethanol absorbed?

In the stomach and small intestine.

Which organs take up ethanol from the bloodstream?

Hepatocytes in the liver, muscle tissue, and brain.

What percentage of ingested ethanol does the liver metabolize?

Over 90 %.

Name the three oxidative pathways of ethanol metabolism.

Alcohol dehydrogenase (ADH), microsomal ethanol-oxidizing system (MEOS, CYP2E1), and catalase.

What is the product common to ADH and MEOS oxidation of ethanol?

Acetyl-CoA.

What non-oxidative ethanol metabolism pathway exists?

Formation of fatty acid ethyl esters by RR ethyl ester synthase.

Why is non-oxidative ethanol metabolism harmful?

It increases damage to the pancreas and liver.

What is the structural nature of alcohol dehydrogenase (ADH)?

A dimeric protein composed of two subunits encoded by different genes.

What determines the substrate specificity of ADH isoenzymes?

The length of the alcohol chain and isozyme activity.

Which ADH class dominates in liver ethanol metabolism?

Class I ADH, with high affinity (Km 0.013–4 mM) and no inhibition by high ethanol levels.

What characterizes the MEOS pathway?

CYP2E1 in the smooth ER, lower ethanol affinity (Km ≈ 11 mM), inducible by chronic alcohol use, generates ROS.

Which enzyme converts acetaldehyde to acetate?

Aldehyde dehydrogenase (ALDH), especially mitochondrial ALDH-2.

What is the Km of ALDH-2 for acetaldehyde?

0.2 μM.

How does ALDH genetic polymorphism affect alcohol tolerance?

A higher Km (e.g., 46 μM) reduces ALDH capacity, causing acetaldehyde buildup, nausea, and vomiting.

What cofactor do heme proteins contain?

Metalloporphyrin

What are the two primary functions of heme proteins?

Electron transfer and oxygen carriage

Name four typical human heme proteins.

Cytochromes, hemoglobin, myoglobin, catalase, and peroxidase