PRINCIPLES OF TOXICOLOGY

62 BIOTRANSFORMATION: A BALANCE BETWEEN BIOACTIVATION AND DETOXIFICATION
3.1 SITES OF BIOTRANSFORMATION
Xenobiotic metabolism occurs in all organs and tissues in the body. Because many of the chemicals
metabolized can have deleterious effects on the body, xenobiotic metabolism can be considered a
defense mechanism that hastens the elimination of a toxic chemical and thus terminates the exposure.
When viewed as a defense mechanism, it is not surprising that the exposure is best terminated at the
point of exposure. These are the so-called portals of entry (shown as sites of absorption [a] for
xenobiotics [X] in Figure 3.1), and constitute mainly the skin, lung, and intestinal mucosa. While drug
metabolizing enzymes are present in all these tissues (Table 3.2), and at relatively high activity in some,
particularly intestine and lung, the liver is by far the most important tissue for xenobiotic metabolism
(site [m] in Figure 3.1).
Although it is not the first tissue of the body to be exposed to chemicals, the liver receives the entire
chemical load absorbed from the gastrointestinal tract, which is the predominant portal of entry for
most xenobiotics (Figure 3.1). The xenobiotic metabolizing enzymes are present in high concentrations
and the organ itself has large bulk, approximately 5 percent of the total body weight. Xenobiotics
absorbed from the lungs and skin can also quickly move to the liver for metabolism. Once in the liver,
the highly vascular nature of the tissue and the intimate contact between blood and hepatocytes, which
contain the xenobiotic metabolizing enzymes, allows for the rapid diffusion of chemicals in and
metabolites out (Figure 3.5).
Although not a portal of entry, the kidney is an organ where xenobiotics are likely to be
concentrated during the excretion process, and this may be the reason for the relatively high level
of xenobiotic metabolizing enzymes in this tissue. Although the data presented in Table 3.2 are
from laboratory animals, there is little evidence to contraindicate the existence of a similar
distribution pattern in humans.
Within the liver, hepatocytes or parenchymal cells are the major site of drug biotransformation,
and within these cells it is the endoplasmic reticulum, which occupies about 15 percent of the
hepatocyte volume and contains 20 percent of the hepatocyte protein, which houses the bulk of
the critical drug metabolizing enzyme activity. (The nonparenchymal cells, including endothelial
and Kupffer cells, constitute 35 percent of liver cell number but only contribute 5–10 percent of
liver mass. Their drug metabolizing enzyme activities are typically less than 20 percent of that in
hepatocytes).
When liver is carefully homogenized, fragments of the endoplasmic reticulum are converted to
microsomes (an artifact of cell disruption). The drug-metabolizing enzymes located in the endoplasmic
reticulum are often referred to as microsomal enzymes, and it is often stated that chemicals are
metabolized by liver microsomes. Enriched microsomal fractions are usually obtained by differential
sedimentation, either as a suspension with cytoplasm (10,000g supernatant) or as a sediment free of
cytosol (105,000g precipitate) (Table 3.3).
Many important xenobiotic metabolizing enzymes reside in the cytoplasm and microsomal fractions
(Figures 3.3 and 3.6).
Oxidations and glucuronidations are the most common reactions occurring in microsomes. The
terminal oxidase responsible for many of the oxidations, cytochrome P450, represents about 5 percent
of the microsomal protein under normal conditions; more if induction has occurred (see text below).
Other flavoproteins necessary for cytochrome P450 function and epoxide hydrolase, an enzyme
important in the further metabolism of epoxides formed by cytochrome P450–dependent oxidation,
are also conveniently located in the endoplasmic reticulum (Figure 3.6). Microsomal metabolism in
tissues other than liver is seldom quantitatively important in overall drug elimination, but local
generation of active metabolites may be important in drug-induced tissue damage, carcinogenesis, and
other effects. Enzymes located in the cytoplasm of the hepatocyte catalyze a wide variety of both phase
I and phase II reactions. Dehydrogenases and esterases are examples of phase I enzymes found
predominantly in the cytosol. The sulfotransferase and glutathione transferase enzymes also depicted
in Figure 3.6 serve as examples of phase II enzymes that are similarly located.