29.1.2.1 Clinical Biomarkers of Hepatotoxicity

The clinical biomarkers of liver damage are represented by the increased plasma or

serum levels of alanine transaminase (ALT), aspartate transaminase (AST), alkaline

phosphate (ALP), bilirubin, albumin, triglycerides and total cholesterol pertinent to

liver damage as they could flow into the blood due to hepatotoxicity (Gutierrezl and

Solis 2009). The magnitude of the elevation and the enzymes involved depend on the

quality and quantity of the impairing agent, the severity and the stage of hepatic

injury. The serum levels of enzymes result from the damaged hepatocytes, as these

enzymes are located in the cell cytoplasm and are released into the bloodstream from

the damaged liver cells (Yousef et al. 2010).

29.1.2.2 The Pharmacometabolomic Impact of Hepatotoxicity

One of the major consequences of ALD is the progressive deterioration of hepatic

structure: first the steatosis, afterwards the hepatitis and finally the cirrhosis. This

cascade results in reduction in hepatic cell mass and consequent decrease in the

functional capacity of the liver. This will influence pharmacokinetic parameters:

reduced metabolic function cause increase in bioavailability of most drugs therefore,

and, in general, decrease in dose and increase in dosage intervals are necessary.

Pharmacodynamics is also affected: the central nervous system of patients with ALD

is more sensitive to sedative and hypnotic effect of drugs; therefore adjustment of

dose and the dosing interval are desired.

29.1.3 Xenobiotic Metabolism by the Liver

A wide range of drugs are metabolized by the liver to water-soluble or less lipid-

soluble products which are further excreted in bile. Biotransformation of xenobiotics

usually occurs in two steps: Phase I (oxidative, reductive or hydrolytic process) and

Phase II (conjugation). Phase I metabolic reactions are mediated by various cyto-

chrome P450 (CYP) enzymes including oxidation, reduction and hydrolysis

reactions.

29.1.3.1 Hepatic Cytochrome P450 Coenzymes

Cytochrome P450 (CYP) coenzymes are a superfamily of monooxygenases that are

found in all zoological kingdoms of life and which show extraordinary diversity in

their reaction chemistry. In mammals, these enzymes are found primarily in the

membranes of the endoplasmic reticulum (microsomes) within liver cells

(hepatocytes), as well as many other cell types. They perform oxidation and reduc-

tion reactions using iron to increase the water solubility of drugs for excretion. They

can also clear the body of metabolic products such as bilirubin, which arises from the

breakdown of haemoglobin. There is a high concentration of CYP proteins in the

liver, but these enzymes are also found throughout the body, where they often have

specialized roles. These enzymes are so named because they are bound to

membranes inside the cell and contain heme pigment which absorbs light at

450 nm on exposure to carbon monoxide. The various forms of CYT P450 are

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