PRINCIPLES OF TOXICOLOGY

BIOTRANSFORMATION: A BALANCE BETWEEN BIOACTIVATION AND DETOXIFICATION 59
Figure 3.2 The role of metabolism in increasing urinary excretion.
excretion of xenobiotics into the urine largely terminates the exposure of the body to the chemical,
excretion in the bile may not always result in efficient drug elimination because enterohepatic
recirculation may occur. This can result in the prolonged effects and persistence seen with some drugs
and chemicals. Enterohepatic recirculation most often involves the secretion of xenobiotic conjugates
in the bile and their hydrolysis by enzymes from the host or microorganisms in the gastrointestinal
tract. This deconjugation releases the free xenobiotic, which is often sufficiently lipid soluble (high
octanol/water partition coefficient), to be reabsorbed. The reabsorbed xenobiotic returns in the portal
circulation to the liver where it is reconjugated, resecreted, and so on. The same reabsorption can also
occur if an unmetabolized lipid soluble xenobiotic is secreted in the bile.
As stated above, the conversion of xenobiotics is divided into the two phases of metabolic transformation
and conjugation (Figure 3.3). The main chemical reactions involved in phase I or metabolic transformation,
in approximate order of capacity or importance, are oxidation, hydrolysis, and reduction. Of the phase II or
conjugation reactions, glucuronidations are generally the most prevalent in mammals, with the other
conjugations having lesser overall capacity. All conjugation reactions, except with glutathione, involve the
participation of energy-rich or activated cosubstrates. Conjugation with the cellular nucleophile, glutathione,
is an especially important mechanism for the sequestering of electrophilic intermediates generated during
phase I metabolism, and it can occur, albeit less efficiently, in the absence of enzyme.
As mentioned above, with reference to the generation of electophilic metabolites, biotransformation can
have a variety of effects on the biological reactivity of the xenobiotic. The chemical can be inactivated or
detoxified, can be changed into a more toxic substance (bioactivated), or can be changed into other chemical
entities having effects that differ both quantitatively and qualitatively from the parent compound (Table 3.1).
Generally, phase II metabolites are inactive, but important exceptions exist. Phase I metabolites
may or may not be inactive, and many are more reactive than the original xenobiotic. The greater
reactivity can be viewed as an unfortunate necessary prerequisite to conjugation, which is the step
contributing most to the facilitation of excretion (Figure 3.4).