PRINCIPLES OF TOXICOLOGY

3 Biotransformation: A Balance between
Bioactivation and Detoxification
BIOTRANSFORMATION: A BALANCE BETWEEN BIOACTIVATION AND DETOXIFICATION
MICHAEL R. FRANKLIN and GAROLD S. YOST
This chapter identifies the fundamental principles of foreign compound (xenobiotic) modification by
the body and discusses
• How xenobiotics enter, circulate, and leave the body
• The sites of metabolism of the xenobiotic within the body
• The chemistry and enzymology of xenobiotic metabolism
• The bioactivation as well as inactivation of xenobiotics during metabolism
• The variations in xenobiotic metabolism resulting from prior or concomitant exposure to
xenobiotics and from physiological factors
The body is continuously exposed to chemicals, both naturally occurring and synthetic, which have
little or no value in sustaining normal biochemistry and cell function. These chemical substances
(xenobiotics) can be absorbed from the environment following inhalation, ingestion in food or water,
or simple exposure to the skin (Figure 3.1). Biotransformation or metabolism of the chemicals allows
the elimination of the absorbed chemicals to occur. Without this process, chemicals that were readily
absorbed through lipid membranes because of a high octanol/water partition coefficients would fail to
leave the body. They would be passively reabsorbed through the lipid membrane of the kidney tubule
instead of remaining in, and passing out with, the urine (Figure 3.2). In addition, they would not be
subject to active transport mechanisms capable of actively secreting many xenobiotic metabolites.
Thus, an important objective of biotransformation is to promote the excretion of chemicals by the
formation of water-soluble metabolites or products. Biotransformation can also alter the biological
activity of chemicals, including endogenous chemicals released in the body, such as steroids and
catecholamines, both by structural alteration and by enhancing their partition away from cellular
compartments, membranes, and receptors. Thus biotransformation helps to both terminate the biological
activity of chemicals and increase their ease of elimination.
Biotransformation is defined as the chemical alteration of substances by reactions in the living
organism. For convenience, the conversion of xenobiotics is divided into two phases: metabolic
transformations (phase I reactions) and conjugation with natural body constituents (phase II reactions)
(Figure 3.3). The reactions of both of these phases are predominantly enzyme-catalyzed. A xenobiotic
does not necessarily undergo metabolism by a sequential combination of phase I followed by phase II
reactions for successful elimination. It may undergo phase I metabolism alone, phase II alone, and
occasionally, phase I reactions subsequent to phase II conjugations are encountered.
An important objective of biotransformation is to promote the excretion of absorbed chemicals by
the formation of water-soluble drug metabolites or products (p in Figure 3.1). Increased water solubility
is derived primarily from the phase II reactions since most conjugates exist in the ionized state at
physiological pH levels. This promotes excretion (e in Figure 3.1) by decreasing xenobiotic reabsorp-
Principles of Toxicology: Environmental and Industrial Applications, Second Edition, Edited by Phillip L. Williams,
Robert C. James, and Stephen M. Roberts.
ISBN 0-471-29321-0 © 2000 John Wiley & Sons, Inc.
57