Page 312 - Industrial Ventilation Design Guidebook

268 CHAPTER 5 PHYSIOLOGICAL AND TOXICOLOGICAL CONSIDERATIONS

compound be metabolized; in most cases small amounts of unchanged parent
compound can also be found in the urine. This can also be utilized as a spe-
cific biological monitoring test. The enzymes responsible for biotransforma-
tion of xenobiotics also catalyze the metabolism of endogenous compounds,
such as hormones and neurotransmitters. For example, steroid hormones un-
dergo phase I oxidation catalyzed by P450 enzymes and then conjugation re-
actions of the functional groups catalyzed by glucuronyltransferase or
sulfotransferase. The number of possible metabolites of various chemicals is
often very large because of the variety of different phase I and phase II en-
63 72
zymes in the cells. '
The highest activities and amounts (the amount of enzyme protein/g pro-
tein in the tissue) of biotransformation enzymes are found in the liver, and this
organ plays a key role in the metabolism of endogenous and foreign com-
pounds. However, these enzymes can be found in many other organs, and one
can hypothesize that enzymes expressed at the entries to the body, i.e., the skin
and the mucosa of the gastrointestinal tract and airways, have developed dur-
ing evolution to protect the organism against foreign compounds. In fact, the
liver and kidneys are also direct or indirect sites of entry of foreign com-
pounds into the body. The liver is an important port of entry because of the
portal vein that carries most foreign compounds directly from the intestine to
the liver. The kidneys can also be a port for chemical compounds into the
body because a number of compounds excreted in the urine may be reab-
sorbed in the proximal tubules of the kidney. Such compounds include those
with an active transport system, many lipid-soluble compounds, and metabo-
lites that have been hydrolyzed in the urine. On the other hand, metabolites of
these parent compounds conjugated with biological macromolecules or amino
68 72
acids are readily excreted in the urine or bile. '
Biologically active compounds are often inactivated during phase I
biotransformation. However, in some instances, biological activity of chemical
compounds may be increased, and they can become activated especially by the
P450 enzyme (CYP enzymes) system that catalyzes oxidation, hydroxylation,
and epoxidation. These reactions may yield electrophilic intermediates that
readily react with the nucleophilic groups of biological macromolecules, such
as nucleic acids and proteins, with toxic consequences, such as cell death, mu~
tagenesis, malignant transformation of cells, or teratogenesis. For example,
activation of carbon tetrachloride, bromobenzene, and acetaminophen {para-
cetamol) after high doses cause liver necrosis. At lower doses, they may cause
genotoxic alterations in the cells and subsequent malignant transformation of
the exposed cells. Active metabolites of aflatoxin Bl (a fungal toxin),
benzo(a)pyrene (a combustion product), and vinyl chloride (a plastic mono-
mer), induce cancer subsequent to their binding with bases in the DNA, Since
all of the compounds that are absorbed in the gastrointestinal tract enter the
liver directly through the portal vein, their biotransformation is very effective
in the liver because of their extensive contact with metabolically active liver
cells, the hepatocytes. The anatomical structure of the liver further promotes
effective biotransformation of xenobiotics in this organ (Fig. 5.38), A number
of factors affect the metabolizing capacity of the liver. These include the con-
centration of phase I CYP enzymes, the uptake of the compounds by the liver