CHAPTER 2

Review of Related Literature and Significance of the Review

Hepatotoxicity of Acetaminophen (Paracetamol)

Humans are exposed daily to a wide variety of foreign compounds called xenobiotics—

substances absorbed across the lungs or skin or, more commonly, ingested either unintentionally as

compounds present in food and drink or deliberately as drugs for therapeutic or “recreational”

purposes. (Katzung,Masters&Trevor,2009)

A process that can lead to the termination or alteration of biologic activity is metabolism.

Metabolism is the total of all the chemical reactions that occur in the body. It consist of

anabolism, the energy-requiring process by which small molecules are joined to form larger ones, and

catabolism, the energy-releasing process by which larger molecules are broken down into smaller ones.

Anabolism occurs in all cells of the body as they divide to form new cells, maintain their own

intracellular structure, and produce molecules such as hormones, neurotransmitters, or extracellular

matrix molecules for export. Catabolism begins during the process of digestion and is concluded within

individual cells. The energy derived from catabolism is used to drive anabolic reactions. Metabolism can

be divided into the chemical reactions that occur during digestion and the chemical reactions that occur

after the products of digestion are taken up by cells. The chemical reactions that occur within cells are

often referred to as cellular metabolism. (Seeley, Stephens, & Tate, 2007)

In general, lipophilic xenobiotics are transformed to more polar and hence more readily

excreted products. The role that metabolism plays in the inactivation of lipid-soluble drugs can be quite

dramatic. Metabolic products are often less pharmacodinamically active than the parent drug and may

even be inactive. However, some biotransformation products have enhanced activity or toxic properties.
It is noteworthy that the synthesis of endogenous substrates such as steroid hormones, cholesterol,

active vitamin D congeners, and bile acids involves many pathways catalyzed by enzymes associated

with the metabolism of xenobiotics. Finally, drug-metabolizing enzymes have been exploited in the

design of pharmacologically inactive prodrugs that are converted to active molecules in the body.

(Katzung,Masters&Trevor,2009)

Although every tissue has some ability to metabolize drugs, the liver is the principal organ of

metabolism.(Katzung,Masters&Trevor,2009) One of the liver’s main function is detoxification of harmful

chemicals. Liver cells remove ammonia from the circulation and convert it to urea, which eliminated in

the urine; other substances are detoxified and secreted in the bile or excreted in the urine. (Seeley,

Stephens, & Tate, 2007) Other tissues that display considerable activity include the gastrointestinal

tract, the lungs, the skin, the kidneys, and the brain. After oral administration, many drugs are absorbed

intact form the small intestine and transported first via the portal system to the liver, where they

undergo extensive metabolism. This process is called first-pass effect. Following absoption across the gut

wall, the portal blood delivers the drug to the liver prior to entry into the systemic circulation. A drug

that can be metabolized in the gut wall (eg, by the CYP3A4 enzyme system) or even in the portal of

blood, but most commonly it is in the liver that is responsible for metabolism before the drug reaches

the systemic circulation. In addition, the liver can excrete the drug into the bile. Any of these sites can

contribute to this reduction in bioavailability, and the overall process is known as first-pass elimination.

(Katzung,Masters&Trevor,2009)

Metabolism of drugs and other foreign chemicals may not always be an innocuous biochemical

event leading to detoxification and elimination of the compound. Indeed, as previously noted, several

compounds have been shown to be metabolically transformed to reactive intermediates that are toxic

to various organs. Such toxic reactions may not be apparent at low levels of exposure to parent
compounds when alternative detoxification mechanism are not yet overwhelmed or compromised and

when the availability of endogenous detoxifying cosubstrates (GSH, glucoronic acid, sulphate) is not

limited. However, when these resources are exhausted, the toxic pathway prevail, resulting in overt

organ toxicity or carcinogenesis. The number of specific examples of such drug-induced toxicity is

expanding rapidly. An example is acetaminophen (paracetamol)-induced hepatotoxicity. A