PRINCIPLES OF TOXICOLOGY

3.2 BIOTRANSFORMATION REACTIONS 75
Stimulation of Xenobiotic-Metabolizing Enzyme Activities by Xenobiotics. The activity of many microsomal
and some cytoplasmic drug metabolizing enzymes can be increased by exposure to a wide
range of drugs and other chemicals (Table 3.6). Generally, inducing agents possess two features in
common: lipid solubility and a relatively long biological half-life (i.e., they gain access to the liver and
remain there for a considerable period of time).
The stimulation of enzyme activity, called induction, is most often the result of the increased amount
of enzyme present. If it is the result of an increased efficiency of existing enzyme it is termed activation,
a phenomenon seen under some conditions with UDP-glucuronosyltransferases. Although not currently
well documented for xenobiotic metabolizing enzymes, the activity of many enzymes can be
altered by structural modification from processes such as phosphorylation by kinases and dephosphorylation
by phosphatases.
Induction occurs by the inducing substance stimulating the synthesis of new enzyme. Because new
protein (enzyme) synthesis requires time, the increase in activity is not an immediate event, and occurs
over a period of many hours or days. Returning to a normal state following induction also takes a
similar time course. The pattern of enzymes induced (both phase I and phase II) and the time course
of induction varies with the agent. Induction is not open-ended, but rather, there appear to be limits to
changes in each individual enzyme. Increases in liver microsomal enzyme activities determined in in
vitro assays are often magnified for the metabolism of the xenobiotic in the whole animal because
accompanying the increased enzyme activity per milligram of membrane protein are increased amounts
of membrane per cell and increased overall size (most often an increased number of cells) of the liver.
The mechanism of induction is best understood for one group of compounds, the polycyclic
aromatic hydrocarbon type of inducers, although this receptor-mediated induction (Figure 3.11) may
not be the only mechanism by which these agents induce.
The cytosol contains a protein that has a high affinity for polycyclic aromatic hydrocarbon-like
molecules. One of the chemicals most extensively utilized for these investigations has been 2,3,7,8,tetrachlorodibenzo-p-dioxin
(TCDD). When the agent binds to this “Ah receptor,” it displaces a
heat-shock protein (hsp90), which enables the receptor to enter the nucleus. Through an interaction
Figure 3.11 Induction of xenobiotic-metabolizing enzymes by polycyclic aromatic hydrocarbons and related
compounds.