The liver is strategically interposed between the general circulation and the digestive tract. It receives 20% to 25% of the volume of blood leaving the heart each minute (the cardiac output) through the portal vein (which delivers absorbed nutrients and other substances from the gastrointestinal tract to the liver) and through the hepatic artery (which delivers blood from the general circulation back to the liver). Potentially toxic agents absorbed from the gut or delivered to the liver by the hepatic artery must pass through this metabolically active organ before they can reach the other organs of the body. The liver’s relatively large size (~3% of total body weight) allows extended residence time in the liver for nutrients to be properly metabolized as well as for potentially harmful substances to be detoxified and prepared for excretion into the urine or feces. Among other functions, therefore, the liver, along with the kidney and gut, is an excretory organ, equipped with a broad spectrum of detoxifying mechanisms. It can, for example, carry out metabolic conversion pathways and utilize secretory systems that allow the excretion of potentially toxic compounds. Concurrently, the liver contains highly specific and selective transport mechanisms for essential nutrients that are required not only to sustain its own energy but to provide physiologically important substrates for the systemic needs of the organism. In addition to the myriad of transport processes within the sinusoidal and canalicular plasma membrane sheets (see below), intracellular hepatocytic transport systems exist in organelles such as endosomes, mitochondria, lysosomes, as well as the nucleus. The sequential transport steps carried out by these organelles include (1) uptake, (2) intracellular binding and sequestration, (3) metabolism, (4) sinusoidal secretion, and (5) biliary excretion. The rate of hepatobiliary transport is determined, in part, by the rate of activity of each of these steps. The overall transport rate is also determined by such factors as hepatic blood flow, plasma protein binding, and the rate of canalicular reabsorption. The various aspects of the major metabolic processes performed by the liver have been discussed in greater detail elsewhere in this text. These previous sources will be referred to as the broad spectrum of the liver’s contributions to overall health and disease is described.

THE WAITING ROOM

Blood from both the portal vein and hepatic artery empty into a common conduit, mixing their contents as they enter the liver sinusoids (Fig. 44.1). The sinusoids are expandable vascular channels that run through the hepatic lobules. They are lined with endothelial cells that have been described as “leaky” because, as blood flows through the sinusoids, the contents of the plasma have relatively free access to the hepatocytes, which are located on the other side of the endothelial cells.

The liver is also an exocrine organ, secreting bile into the biliary drainage system. The hepatocytes secrete bile into the bile canaliculus, whose contents flow parallel to that in the sinusoids but in the opposite direction. The canaliculi empty into the bile ducts. The lumina of the bile ducts then fuse, forming the common bile duct. The common duct then releases bile into the duodenum. Some of the liver’s effluent is stored in the gallbladder and discharged into the duodenum postprandially to aid in digestion.

The entire liver surface is covered by a capsule of connective tissue that branches and extends throughout the liver. This capsule provides support for the blood vessels, lymphatic vessels, and bile ducts that permeate the liver. In addition, this connective tissue sheet subdivides the liver lobes into smaller lobules.

II. Liver Cell Types

The stellate cells are also called perisinusoidal or Ito cells. There are approximately 5 to 20 of these cells per 100 hepatocytes. The stellate cells are lipid-filled cells and serve as the primary storage site for vitamin A. They also control the turnover of hepatic connective tissue and extracellular matrix and regulate the contractility of the sinusoids. When cirrhosis of the liver is present, the stellate cells are stimulated by various signals to increase their synthesis of extracellular matrix material. This, in turn, diffusely infiltrates the liver, eventually interfering with the function of the hepatocytes.

In addition to the blood supply from the portal vein, the liver receives oxygen-rich blood through the hepatic artery; this arterial blood mixes with the blood from the portal vein in the sinusoids. This unusual mixing process gives the liver access to various metabolites ingested and produced in the periphery and secreted into the peripheral circulation, such as glucose, individual amino acids, certain proteins, iron–transferrin complexes, and waste metabolites as well as potential toxins produced during substrate metabolism. As mentioned, fenestrations in the endothelial cells, combined with gaps between the cells, the lack of a basement membrane between the endothelial cells and the hepatocytes, and low portal blood pressure (which results in slow blood flow) contribute to the efficient exchange of compounds between sinusoidal blood and the hepatocyte and clearance of unwanted compounds from the blood. Thus, large molecules targeted for processing, such as serum proteins and chylomicron remnants, can be removed by hepatocytes, degraded, and their components recycled. Similarly, newly synthesized molecules, such as very-low-density lipoprotein (VLDL) and serum proteins, can be easily secreted into the blood. In addition, the liver can convert all of the amino acids found in proteins into glucose, fatty acids, or ketone bodies. The secretion of VLDL by the liver not only delivers excess calories to adipose tissue for storage of fatty acids in triacylglycerol, but it also delivers phospholipids and cholesterol to tissues that are in need of these compounds for the synthesis of cell walls as well as other functions. The secretion of glycoproteins by the liver is accomplished through the liver’s gluconeogenic capacity and its access to a variety of dietary sugars to form the oligosaccharide chains, as well as its access to dietary amino acids with which it synthesizes proteins. Thus, the liver has the capacity to carry out a large number of biosynthetic reactions. It has the biochemical wherewithal to synthesize a myriad of compounds from a broad spectrum of precursors. At the same time, the liver metabolizes compounds into biochemically useful products. Alternatively, it has the ability to degrade and excrete those compounds presented to it that cannot be further used by the body.

Xenobiotics are compounds that have no nutrient value (cannot be used by the body for energy requirements) and are potentially toxic. They are present as natural components of foods or they may be introduced into foods as additives or through processing. Pharmacological and recreational drugs are also xenobiotic compounds. The liver is the principal site in the body for the degradation of these compounds. Because many of these substances are lipophilic, they are oxidized, hydroxylated, or hydrolyzed by enzymes in phase I reactions. Phase I reactions introduce or expose hydroxyl groups or other reactive sites that can be used for conjugation reactions (the phase II reactions). The conjugation reactions add a negatively charged group such as glycine, sulfate, or glucuronic acid to the molecule. Many xenobiotic compounds are transformed through several different pathways. A general scheme of inactivation is shown in Figure 44.2.

The conjugation and inactivation pathways are similar to those used by the liver to inactivate many of its own metabolic waste products. These pathways are intimately related to the biosynthetic cascades that exist in the liver. The liver can synthesize the precursors that are required for conjugation and inactivation reactions from other compounds. For example, sulfation is used by the liver to clear steroid hormones from circulation. The sulfate used for this purpose can be obtained from the degradation of cysteine or methionine.

The liver, kidney, and intestine are the major sites in the body for the biotransformation of xenobiotic compounds. Many xenobiotic compounds contain aromatic rings (such as benzopyrene in tobacco smoke) or heterocyclic ring structures (such as the nitrogen-containing rings of nicotine or pyridoxine) that we are unable to degrade or recycle into useful components. These structures are hydrophobic, causing the molecules to be retained in adipose tissue unless they are sequestered by the liver, kidney, or intestine for biotransformation reactions. Sometimes, however, the phase I and II reactions backfire, and harmless hydrophobic molecules are converted to toxins or potent chemical carcinogens.

1. Cytochrome P450 and Xenobiotic Metabolism

The toxification/detoxification of xenobiotics is accomplished through the activity of a group of enzymes with a broad spectrum of biological activity. Some examples of enzymes involved in xenobiotic transformation are described in Table 44.1. Of the wide variety of enzymes that are involved in xenobiotic metabolism, only the cytochrome P450–dependent mono-oxygenase system is discussed here (see Chapter 33). The cytochrome P450–dependent mono-oxygenase enzymes are determinants in oxidative, peroxidative, and reductive degradation of exogenous (chemicals, carcinogens, pollutants, etc.) and endogenous (steroids, prostaglandins, retinoids, etc.) substances. The key enzymatic constituents of this system are the flavoprotein NADPH-cytochrome P450 oxidoreductase and cytochrome P450 (see Fig. 33.5). The latter is the terminal electron acceptor and substrate-binding site of the microsomal mixed-function oxidase complex, a very versatile catalytic system. The system got its name in 1962 when Omura and Sato found a pigment with unique spectral characteristics derived from liver microsomes of rabbits. When reduced and complexed with carbon monoxide, it exhibited a spectral absorbance maximum at 450 nm.

TABLE 44.1 Examples of Enzymes Used in Biotransformation of Xenobiotic Compounds

The major role of the cytochrome P450 enzymes (see Chapter 33) is to oxidize substrates and introduce oxygen to the structure. Similar reactions can be carried out by other flavin mono-oxygenases that do not contain cytochrome P450.

The human cytochrome P450 enzyme family contains 57 functional genes, which produce proteins with at least 40% sequence homology. These isozymes have different but overlapping specificities. The human enzymes are generally divided into nine major subfamilies, and each of these is further subdivided. For example, in the naming of the principal enzyme involved in the oxidation of ethanol to acetaldehyde, CYP2E1, the CYP denotes the cytochrome P450 family, the 2 denotes the subfamily, the E denotes ethanol, and the 1 denotes the specific isozyme.

The CYP3A4 isoform accounts for 30% to 40% of CYP450 enzymes in the liver and 70% of cytochrome enzymes in gut wall enterocytes. It metabolizes the greatest number of drugs in humans. Specific drugs are substrates for CYP3A4. The concomitant ingestion of two CYP3A4 substrates could potentially induce competition for the binding site, which, in turn, could alter the blood levels of these two agents. The drug with the highest affinity for the enzyme will be preferentially metabolized, whereas the metabolism (and degradation) of the other drug will be reduced. The latter drug’s concentration in the blood will then rise.

Moreover, many substances or drugs impair or inhibit the activity of the CYP3A4 enzyme, thereby impairing the body’s ability to metabolize a drug. Some of the lipid-lowering agents known as the statins (HMG-CoA reductase inhibitors) require CYP3A4 for degradation. Appropriate drug treatment and dosing take into account the normal degradative pathway of the drug. However, a component of grapefruit juice is a potent inhibitor of CYP3A4-mediated drug metabolism. Evidence suggests that if certain statins are regularly taken with grapefruit juice, their level in the blood may increase as much as 15-fold. This marked increase in plasma concentration could increase the muscle and liver toxicity of the statin in question because side effects of the statins appear to be dose-related.

The cytochrome P450 isozymes all have certain features in common:

The detoxification of vinyl chloride provides an example of effective detoxification by a P450 isozyme (ethanol detoxification was discussed in Chapter 33). Vinyl chloride is used in the synthesis of plastics and can cause angiosarcoma in the liver of exposed workers. It is activated in a phase I reaction to a reactive epoxide by a hepatic P450 isozyme (CYP2E1), which can react with guanine in DNA or other cellular molecules. However, it also can be converted to chloroacetaldehyde, conjugated with reduced glutathione, and excreted in a series of phase II reactions (Fig. 44.3).

b. Aflatoxin B₁

Aflatoxin B₁ is an example of a compound that is made more toxic by a cytochrome P450 reaction (CYP2A1). Current research suggests that ingested aflatoxin B₁ in contaminated food (it is produced by a fungus [Aspergillus flavus] that grows on peanuts that may have been stored in damp conditions) is directly involved in hepatocarcinogenesis in humans by introducing a G → T mutation into the p53 gene. Aflatoxin is metabolically activated to its 8,9-epoxide by two different isozymes of cytochrome P450. The epoxide modifies DNA by forming covalent adducts with guanine residues. In addition, the epoxide can combine with lysine residues in proteins and thus is also a hepatotoxin.

c. Acetaminophen

Acetaminophen (Tylenol) is an example of a xenobiotic that is metabolized by the liver for safe excretion; however, it can be toxic if ingested in high doses. The pathways for acetaminophen metabolism are shown in Figure 44.4. As shown in the figure, acetaminophen can be glucuronylated or sulfated for safe excretion by the kidney. However, a cytochrome P450 enzyme produces the toxic intermediate N-acetyl-p-benzoquinoneimine (NAPQI), which can be excreted safely in the urine after conjugation with glutathione.

NAPQI is a dangerous and unstable metabolite that can damage cellular proteins and lead to the death of the hepatocyte. Under normal conditions, when acetaminophen is taken in the correct therapeutic amounts, <10% of the drug forms NAPQI, an amount that can be readily handled by the glutathione detoxifying system (phase II reactions). However, when taken in doses that are potentially toxic, the sulfotransferase and glucuronyl transferase systems are overwhelmed, and more acetaminophen is metabolized through the NAPQI route. When this occurs, the levels of glutathione in the hepatocyte are insufficient to detoxify NAPQI, and hepatocyte death can result.

The enzyme that produces NAPQI, CYP2E1, is induced by alcohol (see Chapter 33, MEOS). Thus, individuals who chronically abuse alcohol have increased sensitivity to acetaminophen toxicity, because a higher percentage of acetaminophen metabolism is directed toward NAPQI, compared with an individual with low levels of CYP2E1. Therefore, even recommended therapeutic doses of acetaminophen can be toxic to these individuals.

Effective treatment for acetaminophen poisoning or overdose involves the use of N-acetyl cysteine. This compound supplies cysteine as a precursor for increased glutathione production, which, in turn, enhances the phase II reactions, which reduces the levels of the toxic intermediate.

C. Regulation of Blood Glucose Levels

One of the primary functions of the liver is to maintain blood glucose concentrations within the normal range. The manner in which the liver accomplishes this has been the subject of previous chapters (Chapters 19, 28, and 34). In brief, the pancreas monitors blood glucose levels and secretes insulin when blood glucose levels rise and glucagon when such levels decrease. These hormones initiate regulatory cascades that affect liver glycogenolysis, glycogen synthesis, glycolysis, and gluconeogenesis. In addition, sustained physiological increases in growth hormone, cortisol, and catecholamine secretion help to sustain normal blood glucose levels during fasting (see Chapter 41).

When blood glucose levels drop, glycolysis and glycogen synthesis are inhibited, and gluconeogenesis and glycogenolysis are activated. Concurrently, fatty acid oxidation is activated to provide energy for glucose synthesis. During an overnight fast, blood glucose levels are maintained primarily by glycogenolysis and, if gluconeogenesis is required, the energy (six ATP molecules are required to produce one molecule of glucose from two molecules of lactate) is obtained by fatty acid oxidation. On insulin release, the opposing pathways are activated such that excess fuels can be stored either as glycogen or fatty acids. The pathways are regulated by the activation or inhibition of two key kinases, the cyclic adenosine monophosphate (cAMP)–dependent protein kinase and the AMP-activated protein kinase (see Fig. 34.8 for a review of these pathways). Recall that the liver can export glucose because it is one of the only two tissues that express glucose 6-phosphatase.

D. Synthesis and Export of Cholesterol and Triacylglycerol

When food supplies are plentiful, hormonal activation leads to fatty acid, triacylglycerol, and cholesterol synthesis. High dietary intake and intestinal absorption of cholesterol compensatorily reduces the rate of hepatic cholesterol synthesis, in which case the liver acts as a recycling depot for sending excess dietary cholesterol to the peripheral tissue when needed as well as accepting cholesterol from these tissues when required. The pathways of cholesterol metabolism were discussed in Chapter 32.

E. Ammonia and the Urea Cycle

The liver is the primary organ for synthesizing urea and thus is the central depot for the disposition of ammonia in the body. Ammonia groups travel to the liver on glutamine and alanine, and the liver converts these ammonia nitrogens to urea for excretion in the urine. The reactions of the urea cycle were discussed in Chapter 36.

Table e-44.1 lists some of the important nitrogen-containing compounds that are primarily synthesized or metabolized by the liver.

F. Formation of Ketone Bodies

The liver is the only organ that can produce ketone bodies, yet it is one of the few that cannot use these molecules for energy production. Ketone bodies are produced when the rate of glucose synthesis is limited (i.e., substrates for gluconeogenesis are limited) and fatty acid oxidation is occurring rapidly. Ketone bodies can cross the blood–brain barrier and become a major fuel for the nervous system under conditions of starvation. Synthesis and metabolism of ketone bodies have been described in Chapter 30.

G. Nucleotide Biosynthesis

The liver can synthesize and salvage all ribonucleotides and deoxyribonucleotides for other cells to use. Certain cells have lost the capacity to produce nucleotides de novo but can use the salvage pathways to convert free bases to nucleotides. The liver can secrete free bases into the circulation for these cells to use for this purpose. Nucleotide synthesis and degradation are discussed in Chapter 39.

H. Synthesis of Blood Proteins

The liver is the primary site of the synthesis of circulating proteins such as albumin and the clotting factors. When liver protein synthesis is compromised, the protein levels in the blood are reduced. Hypoproteinemia may lead to edema because of a decrease in the protein-mediated osmotic pressure in the blood. This, in turn, causes plasma water to leave the circulation and enter (and expand) the interstitial space, leading to edema.

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