PRINCIPLES OF TOXICOLOGY

76 BIOTRANSFORMATION: A BALANCE BETWEEN BIOACTIVATION AND DETOXIFICATION
with a transporter protein (ARNT) in the nucleus, it initiates the transcription of mRNA to a limited
number of proteins, including certain isozymes of cytochrome P450 (e.g., CYP1A isozymes) and UDPglucuronosyltransferase
(GT1), by binding to a regulatory region of these genes. The region of DNA
to which it binds has been termed a xenobiotic response element (XRE). These mRNA molecules move
out of the nucleus and are translated into new proteins on the ribosomes attached to the endoplasmic
reticulum. The burst of mRNA production is usually seen within hours of exposure to the inducing
agent. For increased amounts of active cytochrome P450, a coordinate induction of additional heme
in the mitochondrion is also needed. Much of the information on this induction mechanism arose from
work with the “nonresponsive” strains of mice (e.g., D2, CF-1; see Table 3.6) in which the Ah receptor
appears defective with respect to its affinity for the polycyclic aromatic hydrocarbon. No such
well-defined deficiency has yet been found in rat strains or humans.
The list of compounds that induce drug-metabolizing enzymes in a manner different from that of
polycyclic hydrocarbons is much more extensive and includes chemicals of diverse chemical structure
and biological effect. For some of these groups of chemicals (e.g., phenobarbital), no receptor has so
far been identified. Different isozymes of the chemical/drug-metabolizing enzymes are induced (see
Tables 3.4 and 3.6), and in contrast to the polycyclic hydrocarbons, many cause a marked proliferation
of the endoplasmic reticulum and increase in liver size. Some of the induction seen with many of these
agents has been attributed to a stabilization of existing enzyme in addition to the formation of new
enzyme either via enhanced mRNA production (transcription) or changes in the translation rate of
basal amounts of mRNA.
Nonmicrosomal enzymes, including sulfotransferases, are not induced as extensively as are
microsomal enzymes. Exceptions are the cytosolic GSH transferases, which are induced by a wide
range of agents (see Table 3.6). Extrahepatic microsomal enzymes are induced by a more restricted
number of compounds compared to those that are able to induce liver enzymes, and polycyclic aromatic
hydrocarbon-type induction predominates.
A similar degree of induction of both phase I and phase II enzymes does not always occur and can
result in an imbalance in the ability of phase II reactions to conjugate all the reactive centers generated
by the enhanced phase I activity (e.g., dexamethasone and pregnenolone 16α carbonitrile; Table 3.6).
Sometimes, Phase II enzyme activities are increased with little (e.g., tioconazole, isosafrole; Table 3.6)
or no (e.g., 2,2′-dipyridyl, 3,4-benzoquinoline; Table 3.6) effect on phase I enzymes. Changes in
UDP-glucuronosyltransferases may be preferential for one or the other major isozyme (e.g., GT1 >
GT2 for 5,6-naphthoflavone, 3-methylcholanthrene, and 2,3,6,7- tetrachlorodibenzodioxin; GT2 >
GT1 for troleandomycin, phenobarbital, clotrimazole, and isosafrole). Changes in microsomal UDPglucuronosyltransferase
enzymes may (e.g., clotrimazole, isosafrole, and β-naphthoflavone) or may
not (e.g., fluconazole) be accompanied by major induction of the cytosolic glutathione S-transferase
activity.
The consequences of induction can be diverse. An inducing substance may increase the metabolism
of one or more other xenobiotics and can even increase its own metabolism. Induction of microsomal
enzymes can also enhance the metabolism of endogenous substrates such as steroids and bilirubin.
Thus, induction may be important to consider in multiple drug therapy, chronic toxicity tests, crossover
drug testing, and environmental toxicology. Some drug tolerance is explained by increased inactivation
of the drug by induced enzymes. When major increases in phase I enzymes producing reactive
intermediates are not matched by similar increases in the phase II enzymes responsible for their
sequestration, increased toxicity may result.
Induction is qualitatively, if not quantitatively, similar in most common laboratory animal species,
although the rat is perhaps the most responsive (see Table 3.7). Induction is known to occur in humans,
often necessitating a change in the therapeutic dosage regimen of drugs. However, for some agents
(e.g., peroxisome proliferators), the inductive response seen in experimental animals is absent in
humans at therapeutic doses.
Although small differences are evident, the effects of inducers are also similar between strains of
a species and between species. Thus, information derived from studies in one laboratory animal species
can generally be assumed to occur in another. From the examples given in Table 3.7, the phenobarbi-