PRINCIPLES OF TOXICOLOGY

een shown to be responsible for the production of glucuronides, which, via protein alkylation, can
result in the formation of immunogens. The immune response mounted to these aberrant molecules
can be highly toxic to organisms. Examples of toxic conjugates (acyl-linked glucuronides and
glutathione adducts) are shown in Figure 3.13 and Table 3.11. Glutathione conjugates can also serve
as transport forms of reactive intermediates. Methyl isocyanate, a highly reactive electrophile, is such
an example. The glutathione conjugate is transported to sites distant from the initial absorption site to
cause toxicity to other organs.
The balance between detoxication and bioactivation of xenobiotics by metabolism enzymes can be
dramatically changed by the induction or inhibition of the enzymes. Enzymes that are normally present
at low levels, and therefore do not bioactivate toxicants to reactive intermediates, can become active
participants in the toxicity of chemicals when the levels and activities of the enzymes are increased.
Many examples of this situation exist. For example, induction of CYP2E1 by ethanol results in the
greater bioactivation of hepatotoxins like CCl 4 and acetaminophen or carcinogens such as dimethylnitrosamine.
Although the toxicants can produce damage normally, their potency is greatly increased
after induction of CYP2E1; specifically, toxicity is elicited at much lower doses because more of the
chemical is oxidized to a reactive intermediate.
Conversely, the toxicity of many chemicals can be ameliorated by induction of enzymes that are
responsible for the detoxication of the compound. Bilirubin can cause significant central nervous
system damage in neonates where the UDP-glucuronosyltransferase(s) that detoxify this naturally
occurring heme breakdown product are present in low amounts. Inducing the levels of the necessary
UDP-glucuronosyltransferase by drugs such as phenobarbital increases the glucuronidation of bilirubin
and decrease its toxicity. In the same way that induction of bioactivation enzymes can increase
toxicity and induction of detoxification enzymes can decrease toxicity, the inhibition of bioactivation
enzymes or the inhibition of detoxification enzymes should decrease or increase toxicity, respectively.
The carcinogenicity of complex mixtures of polycyclic aromatic hydrocarbons is sometimes found to
be less than one would expect if the relative carcinogenicity of each component were summed. A
probable reason for this decrease in toxicity lies in the inhibition, by components of the mixture, of
the cytochrome P450 enzymes that bioactivate the carcinogens to their DNA-reactive intermediates.
The mechanisms by which xenobiotics cause toxicity can be highly diverse, and elucidating the
precise biochemical and chemical mechanisms that induce toxicity can be a difficult process. There
are many tools available that can be used to evaluate toxic mechanisms. They include the use of animal
species, gender, or cellular differences that vary widely in their response to the toxin. For example,
naphthalene is highly toxic to mice when administered by the intraperitoneal route or by inhalation
but is much less toxic to rats. Investigators have used this species differences to provide vital
information about a cytochrome P450 (CYP2F2) that is highly expressed only in murine lung and is
responsible for the bioactivation of this toxicant. Limonene causes severe renal toxicity to male rats
but not female rats. The primary cause for the toxicity was eventually linked to the expression of a
globulin that is not expressed to a significant degree in female rats. An example of the use of specific
cellular targets is with the nephrotoxic glutathione conjugates of halogenated hydrocarbons, such as
hexachlorobutadiene, which are selective for the proximal tubule cells of the nephron. Analysis showed
that these cells contain high amounts of the enzyme C-S lyase, and it is this enzyme which is responsible
for the production of the electrophilic intermediates from these toxicants. Similarly, it is the high
content of monoamine oxidase B in dopamine-containing neurons linked with the cellular selectivity
of the toxicity of MPTP that has enabled the mechanism of bioactivation of this toxicant to be
elucidated.
3.3 SUMMARY
3.3 SUMMARY 85
By altering a portion of a chemical or by adding another molecule to it, drug-metabolizing enzymes
can alter the toxicity of the chemical, its tissue-binding properties, and its distribution and duration
within the body.