Chapter 6
Biotransformation – Metabolism of
Xenobiotics
6.1 INTRODUCTION
Metabolism is defined as the sum of all chemical reactions that occur within a
living cell. The purpose of cellular metabolism is to maintain the homeostasis
of the cell within a population of other cells. Homeostasis refers to a tendency
toward maintenance of a relatively stable internal environment in the bodies
of higher animals through a series of interacting physiological processes.
Metabolism is usually subdivided into two categories: anabolism and
catabolism. Anabolism is the synthesis of larger molecules from smaller ones.
The synthesis of a protein from its amino acid building blocks is an example.
Anabolism generally requires input of energy from an energy source, such as
ATP. Catabolism refers to the degradation of larger molecules to smaller ones,
e.g., the breakdown of starch to glucose. In higher organisms, catabolism of
carbohydrates and fats results in the production of ATP.
Following their absorption into a mammal, xenobiotics are subjected to
metabolic conversion in the body, resulting in structural changes. This
metabolic process is called biotransformation. Biotransformation may occur
in any of several body tissues and organs, including skin, lung, intestine, liver,
and kidney. The liver carries out the majority of the chemical reactions because
it contains a large number of nonspecific enzymes capable of biotransformation of xenobiotics. The enzymes involved in the biotransformation are named
mixed-function oxidase (MFO), commonly known as cytochrome P450. The
liver metabolizes not only many xenobiotics, but also drugs to which the body
is exposed. Biotransformation in the liver is thus a critical process in the body’s
defense against the toxic effects of a wide variety of xenobiotics.
1
6.2 TYPES OF BIOTRANSFORMATION
As mentioned in Chapter 4, the process of xenobiotic biotransformation
consists of two phases: Phase I and Phase II (Figure 6.1). Phase I biotransformation includes oxidation, reduction, and hydrolysis. Phase II
biotransformation is essentially composed of conjugation reactions.
Among the representative oxidation reactions catalyzed by cytochrome
P450 are hydroxylation (of an aliphatic or aromatic carbon), dealkylation
(including atoms such as O, S, or N), deamination, epoxidation, oxidative
[16:53 26/8/04 P:/CRC PRESS/4365 MING-HO.751 (1670)/4365-006.3d]
Ref: 4365 MING-HO YU Chap-006 Page: 85 85-98
85
Biotransformation – Metabolism of
Xenobiotics
6.1 INTRODUCTION
Metabolism is defined as the sum of all chemical reactions that occur within a
living cell. The purpose of cellular metabolism is to maintain the homeostasis
of the cell within a population of other cells. Homeostasis refers to a tendency
toward maintenance of a relatively stable internal environment in the bodies
of higher animals through a series of interacting physiological processes.
Metabolism is usually subdivided into two categories: anabolism and
catabolism. Anabolism is the synthesis of larger molecules from smaller ones.
The synthesis of a protein from its amino acid building blocks is an example.
Anabolism generally requires input of energy from an energy source, such as
ATP. Catabolism refers to the degradation of larger molecules to smaller ones,
e.g., the breakdown of starch to glucose. In higher organisms, catabolism of
carbohydrates and fats results in the production of ATP.
Following their absorption into a mammal, xenobiotics are subjected to
metabolic conversion in the body, resulting in structural changes. This
metabolic process is called biotransformation. Biotransformation may occur
in any of several body tissues and organs, including skin, lung, intestine, liver,
and kidney. The liver carries out the majority of the chemical reactions because
it contains a large number of nonspecific enzymes capable of biotransformation of xenobiotics. The enzymes involved in the biotransformation are named
mixed-function oxidase (MFO), commonly known as cytochrome P450. The
liver metabolizes not only many xenobiotics, but also drugs to which the body
is exposed. Biotransformation in the liver is thus a critical process in the body’s
defense against the toxic effects of a wide variety of xenobiotics.
1
6.2 TYPES OF BIOTRANSFORMATION
As mentioned in Chapter 4, the process of xenobiotic biotransformation
consists of two phases: Phase I and Phase II (Figure 6.1). Phase I biotransformation includes oxidation, reduction, and hydrolysis. Phase II
biotransformation is essentially composed of conjugation reactions.
Among the representative oxidation reactions catalyzed by cytochrome
P450 are hydroxylation (of an aliphatic or aromatic carbon), dealkylation
(including atoms such as O, S, or N), deamination, epoxidation, oxidative
[16:53 26/8/04 P:/CRC PRESS/4365 MING-HO.751 (1670)/4365-006.3d]
Ref: 4365 MING-HO YU Chap-006 Page: 85 85-98
85