Liver Functions

Spec Mapping — OCR H420 Module 5.1.2 — Excretion, content statements covering the principal biochemical functions of the mammalian liver — detoxification, deamination of excess amino acids, and the conversion of ammonia to urea via the ornithine cycle (refer to the official OCR H420 specification document for exact wording).

The liver performs hundreds of distinct biochemical functions, but three of them are central to the OCR specification: detoxification, deamination of excess amino acids, and the ornithine cycle that converts toxic ammonia to urea. These illustrate perfectly how a single organ can integrate nutrient processing, waste disposal and biosynthesis. This lesson covers these key functions in the depth expected for A-Level, with named enzymes, substrates and products, matching OCR A-Level Biology A specification module 5.1.2(d).

The urea cycle was elucidated in 1932 by Hans Krebs and Kurt Henseleit, working in Freiburg using rat liver slices. By feeding the liver slices defined amino acids and observing which would stimulate urea production, they showed that a small set of intermediates (ornithine, citrulline, arginine) acted catalytically — each turnover regenerating ornithine, exactly as Krebs would later show for the citric-acid cycle (1937). The ornithine cycle was thus the first biochemical cycle to be described, and remains a model for how biochemists deduce cyclic mechanisms from steady-state kinetics. The historical work is paraphrased here; original publications are not quoted verbatim.

Key Definitions:

• Detoxification — the chemical modification of toxic substances so they can be safely excreted or used.
• Deamination — the removal of the amino group (−NH₂) from an amino acid.
• Ornithine cycle — the sequence of reactions in hepatocytes that combines ammonia with CO₂ to form urea.
• Dehydrogenase — an enzyme that catalyses the removal of hydrogen from a substrate, usually passing it to NAD⁺.

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An Overview of Liver Functions

Before focusing on the three OCR functions, it helps to appreciate the breadth of the liver's work:

Function	Example
Nutrient processing	Converts glucose to glycogen for storage (glycogenesis); releases glucose when needed (glycogenolysis); makes glucose from non-carbohydrate sources (gluconeogenesis).
Lipid metabolism	Synthesises cholesterol, bile salts and lipoproteins; β-oxidation of fatty acids.
Protein synthesis	Produces plasma proteins (albumin, clotting factors, transport proteins).
Detoxification	Modifies alcohol, drugs, hormones and toxins for excretion.
Deamination	Removes amino groups from surplus amino acids and converts them to urea.
Storage	Stores iron, vitamins A, D, B₁₂, and glycogen.
Bile production	Produces bile containing bile salts and bile pigments.
Immune function	Kupffer cells phagocytose bacteria and old red blood cells.

OCR focuses on detoxification, deamination and the ornithine cycle — but awareness of this wider context helps you understand why exam questions often integrate liver function with other topics.

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Detoxification

Detoxification is the chemical transformation of potentially harmful substances into less harmful (or more easily excreted) compounds. These include:

• Alcohol (ethanol) from drinks.
• Drugs such as paracetamol, antibiotics and anaesthetics.
• Hormones that have already had their effect and must be inactivated (e.g., oestrogen, cortisol, insulin).
• Toxins produced by gut bacteria or absorbed from food (e.g., ammonia, food colourings).

Most detoxification reactions occur in the smooth endoplasmic reticulum (SER) of hepatocytes, where specific enzymes catalyse:

• Oxidation (adding oxygen or removing hydrogen).
• Reduction (adding hydrogen).
• Hydrolysis (breaking bonds with water).
• Conjugation (attaching a water-soluble molecule such as glucuronic acid to aid excretion).

The Breakdown of Alcohol

Alcohol (ethanol) is the classic detoxification example and the one OCR most commonly asks about.

flowchart LR
    A["Ethanol<br/>CH3CH2OH"] -->|alcohol dehydrogenase<br/>NAD+ → NADH| B["Ethanal<br/>CH3CHO"]
    B -->|aldehyde dehydrogenase<br/>NAD+ → NADH| C["Ethanoate<br/>CH3COO-"]
    C -->|+ CoA, ATP| D[Acetyl CoA]
    D --> E["Krebs cycle<br/>or fatty acid synthesis"]

1. Ethanol → ethanal. Catalysed by alcohol dehydrogenase (ADH) in the cytoplasm of hepatocytes. Hydrogen is removed from the ethanol molecule and transferred to NAD⁺, forming NADH + H⁺. The product, ethanal (acetaldehyde), is itself toxic — responsible for many of the symptoms of a hangover.
2. Ethanal → ethanoate. Catalysed by aldehyde dehydrogenase (ALDH) in mitochondria. Again, hydrogen is removed and transferred to NAD⁺. The product is ethanoate (acetate).
3. Ethanoate → acetyl CoA. Ethanoate is combined with coenzyme A to form acetyl CoA, which can enter the Krebs cycle to release energy, or be used to synthesise fatty acids for storage.

Consequences of Heavy Drinking

Chronic alcohol consumption has predictable consequences based on this pathway:

• Each step produces NADH. A high NADH:NAD⁺ ratio inhibits fatty acid oxidation and promotes fatty acid synthesis. The result is fatty liver (steatosis).
• Fatty acids accumulate in hepatocytes, causing inflammation (alcoholic hepatitis).
• Long-term damage triggers stellate cells to deposit collagen — scar tissue replaces functional hepatocytes (cirrhosis), which is irreversible.
• Ethanal is toxic and mutagenic, contributing to hepatic injury.

OCR questions often ask you to explain why alcohol causes fatty liver. The answer lies in the disturbed NAD⁺/NADH balance, not merely in "ingesting fat".

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Deamination

Mammals cannot store excess amino acids. Protein eaten in excess of the body's needs must therefore be disposed of. The liver performs this through deamination: the removal of the amino group (−NH₂) from each excess amino acid.

The Reaction

In simplified form:

$\text{amino acid} + \text{O}_2 \rightarrow \text{keto acid} + \text{NH}_3$amino acid+O2​→keto acid+NH3​

• The amino group is removed as ammonia (NH₃). Ammonia is extremely toxic, so it is immediately fed into the ornithine cycle (see below) for conversion to urea.
• The remaining carbon skeleton is a keto acid, which enters central metabolism. It can be used for respiration (converted to pyruvate or Krebs cycle intermediates), for gluconeogenesis, or for the synthesis of fatty acids.

Deamination therefore links protein metabolism to energy metabolism — the carbon skeletons of amino acids are not wasted but are recycled into ATP production or fat storage.

Transdeamination

In most amino acids, the amino group is first transferred to α-ketoglutarate, forming glutamate, in a reaction catalysed by transaminases (aminotransferases). Glutamate is then oxidatively deaminated by glutamate dehydrogenase, releasing the amino group as ammonia and regenerating α-ketoglutarate. This two-step process is called transdeamination and it funnels amino groups from many amino acids into a single ammonia-producing reaction.

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The Ornithine Cycle (Urea Cycle)

Ammonia produced by deamination cannot be allowed to accumulate. Hepatocytes convert it immediately to urea, a much less toxic molecule that can be carried safely in the blood to the kidneys for excretion. The sequence of reactions is known as the ornithine cycle, first described by Krebs and Henseleit in 1932.

The Reactions

flowchart LR
    A[Ornithine] -->|+ NH3 + CO2| B[Citrulline]
    B -->|+ NH3| C[Arginine]
    C -->|+ H2O| D[Urea]
    D -.released.-> E[Blood → Kidneys]
    C -->|hydrolysed| A

Step-by-step:

1. Ornithine + ammonia + carbon dioxide → citrulline. A molecule of ornithine picks up one ammonia molecule and one CO₂ molecule, producing citrulline and releasing water.
2. Citrulline + ammonia → arginine. A second ammonia is added to citrulline, producing arginine.
3. Arginine + water → urea + ornithine. Arginine is hydrolysed, releasing a molecule of urea and regenerating ornithine. The regenerated ornithine can then accept another ammonia, and the cycle continues.

Overall Equation

The overall reaction is:

$2\text{NH}_3 + \text{CO}_2 \rightarrow \text{CO(NH}_2\text{)}_2 + \text{H}_2\text{O}$2NH3​+CO2​→CO(NH2​)2​+H2​O

Each turn of the cycle consumes two ammonia molecules and one CO₂, producing one molecule of urea. Urea diffuses from the hepatocytes into the blood and is carried to the kidneys, where it is filtered and excreted in urine.

Energy Cost

The ornithine cycle is energetically expensive — each urea molecule costs the equivalent of ~4 ATP molecules. This is a price mammals willingly pay in order to convert highly toxic ammonia into a safely excretable waste.

Biological Significance

• Protects the body from ammonia toxicity. Free ammonia disrupts enzyme function and alters cellular pH, especially in the brain.
• Allows protein to be used as fuel. Without the ornithine cycle, mammals could not safely metabolise excess amino acids.
• Explains urea's properties. Urea is highly soluble, uncharged at physiological pH, and diffuses readily — ideal for a transportable waste molecule.

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Relating Liver Structure to These Functions

The liver's structural features support its functions directly:

• Dual blood supply ensures a constant supply of oxygen (for detoxification reactions and the ornithine cycle) and of nutrients to be processed.
• Sinusoids bring blood into close contact with hepatocytes, enabling extraction of amino acids, alcohol and ammonia.
• Hepatocyte microvilli increase surface area for absorption of substances from the sinusoids.
• Abundant SER houses the cytochrome P450 enzymes and alcohol dehydrogenase needed for detoxification.
• Abundant mitochondria provide ATP for the ornithine cycle and contain aldehyde dehydrogenase.
• Kupffer cells remove bacteria and old red blood cells, producing some of the raw materials for bile pigment production.

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Exam Tip

OCR often asks you to give the products of each step of the ornithine cycle. Learn the sequence ornithine → citrulline → arginine → urea + ornithine as a chant. Recall that urea has the empirical formula CO(NH₂)₂, arises from two ammonia molecules and one CO₂, and is produced in the liver but excreted by the kidney.

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Common Exam Mistakes

• Saying the liver "destroys" alcohol. The liver does not destroy it; it oxidises it to ethanoate, which is then used as a fuel.
• Writing "enzymes break down alcohol" without naming them. At A-Level, name alcohol dehydrogenase and aldehyde dehydrogenase.
• Describing deamination as the removal of nitrogen. It removes the amine group (−NH₂), not "nitrogen".
• Confusing the ornithine cycle with the Krebs cycle. The ornithine cycle is for urea production; the Krebs cycle is for aerobic respiration.
• Forgetting that ornithine is regenerated. The cycle name reflects this — each turn regenerates the starting molecule.
• Claiming the liver excretes urea. The liver produces urea; the kidney excretes it.
• Ignoring the role of NAD⁺. Disturbed NAD⁺/NADH balance is the mechanistic cause of alcoholic fatty liver.

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Quick Recap

• The liver detoxifies drugs, hormones and toxins using enzymes in the smooth ER. Alcohol is oxidised to ethanal by alcohol dehydrogenase and then to ethanoate by aldehyde dehydrogenase, both using NAD⁺.
• Deamination removes the −NH₂ group from excess amino acids, producing a keto acid (used in respiration or fat synthesis) and ammonia (fed into the ornithine cycle).
• The ornithine cycle converts two molecules of ammonia and one of CO₂ into one molecule of urea, via the intermediates citrulline and arginine, with ornithine regenerated at the end.
• Urea is carried in the blood to the kidneys, where it is excreted.
• The liver's detailed cellular structure — abundant SER, RER, mitochondria and sinusoidal exposure — enables all of these functions.

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SVG — Nitrogen Flow Through the Hepatocyte